Stable concentrated radiopharmaceutical compositions

Abstract

To provide a radionuclide complex solution of high concentration and high chemical stability which can be used as a medicine for diagnosis and / or treatment.SOLUTION: Provided is a pharmaceutical composition comprising: (a) a complex formed by: (ai) a radionuclide; and (aii) a gastrin releasing peptide receptor peptide antagonist binding moiety linked to a chelating agent; (b) at least two stabilizers against radiolysis; and (c) optionally a surfactant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure provides high concentration chemotherapeutic agents that can be used as commercially available pharmaceuticals for diagnostic and / or therapeutic purposes. and radiolabeled GRPR antagonist compounds with high chemical and radiochemical stability. It relates to pharmaceutical compositions. [Background technology]

[0002] Bombesin was first discovered in the European frog Bombina bombina bombina) and mammalian gastrin-releasing peptide (GRP) and It has been demonstrated to mimic euromedin B (NMB) [Scopinaro F, et al.Eur J Nucl Med Mol Imaging 2003,30(1 0):1378-1382].

[0003] Gastrin-releasing peptide (GRP), a bombesin-like peptide growth factor, is a gastrin-releasing peptide that acts as a gastrointestinal hormone receptor. gastrointestinal system and central nervous system, including the release of hormones, contraction of smooth muscle cells, and proliferation of epithelial cells GRPs are potent mitogens for physiological and neoplastic tissues. It is a phenotype that may be involved in growth dysregulation and carcinogenesis.

[0004] The action of GRP is mediated by its receptor, the GRP receptor (GRPR) (derived from a small cell lung cancer cell line). GRP / Upregulation of the GRPR pathway has been shown to be associated with breast, prostate, uterine, ovarian, and colon cancers. Pancreatic cancer, gastric cancer, lung (small cell and non-small cell) cancer, head and neck squamous cell carcinoma, and various brain and cerebral tumors It has been reported in several cancers, including transtumoral. In breast cancer, overexpression of GRPR can reach extremely high densities depending on the tumor type (e.g., 70-90% expression in ductal carcinoma specimens) [Van de Wiele C, et al .J Nucl Med 2001,42(11):1722-1727].

[0005] GRPR is highly overexpressed in prostate cancer, and in human prostate cancer cells High affinity (nM level) and high tumor take have been demonstrated in studies in cell lines and xenograft models. Both the incidence (%ID / g) and incidence (%ID / g) of HIV-1 infection were shown, spanning the early to late stages of the disease. The relative expression of GRPRs is still not fully understood [Waters, et al. l.2003,Br J Cancer.Jun 2;88(11):1808-181 6].

[0006] In colorectal patients, the presence of GRP and expression of GRPR are important in patients with colorectal cancer, including LN and metastatic lesions. As determined by immunohistochemistry in randomly selected colon cancer samples, >80% of the samples abnormally expressed either GRP or GRPR, and over 60% abnormally expressed both GRP and GRPR. However, expression was not observed in the adjacent normal healthy epithelium [Scopina ro F,et al.Cancer Biother Radiopharm 200 2,17(3):327-335].

[0007] GRP is physiologically present in pulmonary neuroendocrine cells and plays a role in stimulating lung development and maturation. However, GRPs may also be involved in growth dysregulation and carcinogenesis. Stimulation of RP increases the release of epidermal growth factor receptor (EGFR) ligands, followed by EGFR. Activates FR and downstream pathways of mitogen-activated protein kinase. Non-small cell lung cancer Using NSCLC cell lines, both EGF and GRP stimulated the proliferation of NSCLC. It has been confirmed that inhibition of either EGFR or GRPR results in cell death. It has been recognized [Shariati F, et al. Nucl Med Commun 2014,35(6):620-625].

[0008] In nuclear medicine, peptide receptor agonists have long been the drug of choice for tracer development and use. The rationale behind the use of agonist-based constructs is Internalization of the receptor-radioligand complex can result in high accumulation of radioactivity within target cells In the case of radionuclide-labeled peptides, the Efficient receptor-mediated endocytosis is the key to optimal imaging of malignant tumors. The most important requirement is to achieve high in vivo radioactivity uptake in the target tissue. However, receptor-selective peptide antagonists are highly potent agonists. showed favorable biodistribution, including significantly greater in vivo tumor uptake compared to A paradigm shift occurred. The acute adverse biological effects of antagonist use were no longer anticipated. An additional advantage offered by GRPR antagonists is that they are safer and do not Clinical use, which is less in terms of current diagnostic tracer doses However, this is likely in view of larger doses for potential therapeutic purposes [Stoyko w C,et al.Theranostics 2016,6(10):1641-1 650].

[0009] Recently, some GRPR antagonists, such as NeoB, have been radiolabeled with various radionuclides. and imaging of GRPR-expressing cancers, including, but not limited to, prostate cancer and breast cancer. It has become clear that this technology has the potential to be used in sizing and treatment.

[0010] In non-clinical models, 68 Ga]-NeoB and [ 177 Lu]-NeoB is High affinity for GRPR expressed in the rectum, prostate, and gastrointestinal stromal tumors (GISTs) In addition, it showed low internalization upon binding to specific receptors. The ability to target R-expressing tumors was confirmed by in vivo imaging and in vivo analysis in animal models. This has been confirmed by fabric testing [Dalm et al. Journal of nuclea r medicine 2017,Vol.58(2):293-299].

[0011] In this radiopharmaceutical application, the target cell receptor binding moiety is typically a metal ion of a radionuclide. This radiopharmaceutical is then linked to a chelating agent that can form a strong complex with The drug is delivered to the target cell and released by the decay of the radionuclide, followed by high-energy electrons, positrons, and Children, or alpha particles, and gamma rays are emitted at the target site.

[0012] One of the technical problems with these radiopharmaceuticals is that the radionuclide decays constantly (e.g., The high energy emissions released are generated during medical This induces the breaking of chemical bonds in molecules that form part of the drug. Radiolysis or radiolytic degradat Radiolysis of the receptor-binding portion of a drug is called radiolysis. This can result in a decrease in the effectiveness of the drug to act as a steroid.

[0013] These radiopharmaceuticals have low stability and do not have a significant shelf life. So far, these drugs have been manufactured in hospital compounding labs as individual patient doses. and administered immediately to patients already awaiting radiation treatment who need to be at the hospital. This was what was required.

[0014] To reduce radiolysis of radiopharmaceuticals and thereby improve their stability, various Strategies have been explored with more or less success: drugs must be stored at low temperatures or at high dilution rates. It can be produced at high temperature or with the addition of stabilizers.

[0015] However, when stabilizers are added, these chemicals can inhibit the chelating activity of radionuclides. It may adversely affect complexation or become solubility-limiting and precipitate out of solution. This can be problematic as ethanol is reported to be a stabilizer against radiolysis. (International Publication No. 2008 / 009444) Ethanol acts as a complexing agent. Or the amount of ethanol in the injection solution may not adversely affect the solubility issue. High levels of steroids may cause physiological problems and may adversely affect the tolerability of drugs. do.

[0016] The production of pharmaceuticals at high dilutions has the drawback of requiring large volumes of infusion solution to be administered to patients. For reasons of patient convenience and drug tolerability, it is desirable to provide radiopharmaceuticals in high concentrations. However, these highly concentrated solutions are prone to damage, especially from radiolysis. Therefore, on the one hand, pharmaceuticals are diluted to avoid radiolysis. On the other hand, by providing a concentrated drug solution, it avoids patient discomfort during the procedure. This contradictory situation exists. Mathur et al. Cancer Biother apy and Radiopharmaceuticals,2017,32(7), 266-273 reported highly concentrated products and claimed to be readily available. However, the composition contains a large amount of ethanol, which can be difficult to tolerate. There may be issues with sexuality.

[0017] It can therefore be produced on a commercial scale and given in small injection volumes that are convenient for patients. It can be delivered as a highly concentrated, sterile solution that is sufficiently stable to be physiologically well tolerated. A ready-to-use radiopharmaceutical composition having a Designing a composition remains a challenge.

[0018] Recently, the inventors have demonstrated that chemical and radioactive materials can withstand storage at ambient temperature or at elevated temperatures for short periods. It is radiochemically extremely stable and, as a result, can be produced on a commercial scale and used immediately. Method for designing and producing highly concentrated radionuclide complex solutions that can be delivered as pharmaceuticals found. Summary of the Invention

[0019] The present disclosure is provided in various aspects as generally outlined below: 1. (a) Below: (ai) a radionuclide; (aii) a GRP receptor peptide antagonist binding moiety linked to a chelator; and The complex formed thereby; (b) at least two stabilizers against radiolysis; (c) optionally a surfactant.

[0020] 2. The radioactive nuclide is 111 In, 18 F, 211 At, 82 Rb, 123 I, 13 1 I, 133 mIn, 99 mTc, 94 mTc, 67 Ga, 66 Ga, 68 Ga, 52 F e. 169 Er, 72 As, 97 Ru, 203 Pb, 212 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52 mmn, 157 G d. 177 Lu, 161 Tb, 69 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117 mSn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 89 Zr , 225 Ac, 43 Sc, 44 Sc, and 47 Sc, preferably 111 In , 177 Lu, 225 Ac, and 68 Ga, more preferably 177 Lu 2. The pharmaceutical composition of embodiment 1,

[0021] 3. The radionuclides are at least 370MBq / mL (at EOP) ± 37MBq / mL 10. The pharmaceutical composition of embodiment 1, present in a concentration that results in a volumetric radioactivity of 100 mL (±10%). thing.

[0022] 4. The chelating agent is DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA. .

[0023] 5. The GRP receptor peptide antagonist binding moiety linked to the chelator has the formula The pharmaceutical composition of embodiment 1, wherein the NeoB is (I). [ka]

[0024] 6. The at least two stabilizers are gentisic acid (2,5-dihydroxybenzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g., Sodium ascorbate), methionine, histidine, melatonin ne), ethanol, and Se-methionine, preferably gentisic acid or 2. The pharmaceutical composition of embodiment 1, wherein the compound is selected from the group consisting of ascorbic acid or a salt thereof and ascorbic acid or a salt thereof.

[0025] 7. The at least two stabilizers are gentisic acid or a salt thereof and ascorbic acid or The pharmaceutical composition of embodiment 6, which is a salt thereof.

[0026] 8. The ratio between gentisic acid and ascorbic acid is 1:16 to 1:10, typically 1 8. The pharmaceutical composition according to embodiment 7, wherein the DMSO concentration is 1:15 to 1:10, for example 1:12 to 1:11.

[0027] 9. The gentisic acid or salt thereof is at least 1000 μg / mL, for example 1000 μg / 9. The pharmaceutical composition of embodiment 7 or 8, wherein the composition is present in a concentration of from 1000 μg / mL to 1500 μg / mL.

[0028] 10. The ascorbic acid or its salt is at least 10,000 μg / mL, preferably is at least 12000 μg / mL, preferably at least 15000 μg / mL, e.g. Any one of embodiments 7 to 9, wherein the compound is present in a concentration of, for example, 12,000 to 18,000 μg / mL. The pharmaceutical composition described in

[0029] 11. The gentisic acid or salt thereof is at least 1000 μg / mL, for example 1000 μg / mL to 1500μg / mL, and ascorbic acid or a salt thereof is present in a concentration of 15000 12000-18000 μg / mL, for example, in embodiments 7- 10. A pharmaceutical composition according to any one of claims 1 to 10.

[0030] 12. The pharmaceutical preparation has a solubility of more than 95% for up to 72 hours, preferably 98% for up to 72 hours. 12. The pharmaceutical composition according to any one of embodiments 1 to 11, having a radiochemical purity of greater than 1000 mg / kg.

[0031] 13. Any of embodiments 1 to 12, wherein the surfactant is a nonionic surfactant. 1. The pharmaceutical composition described in Item 1.

[0032] 14. The nonionic surfactant is macrogol 15 hydroxystearate, poly Polysorbate 20, polysorbate 80, or polysorbate with an average molecular weight of 10,000 14. The pharmaceutical composition of embodiment 13, wherein the compound is selected from polyvinylpyrrolidone.

[0033] 15. The nonionic surfactant is macrogol 15-hydroxystearate. , The pharmaceutical composition according to embodiment 14.

[0034] 16. The surfactant is at least 5 μg / mL, preferably at least 25 μg / mL 16. The method of claim 1, wherein the hydroxybenzoate is present in a concentration of at least 50 μg / mL, more preferably at least 50 μg / mL. The pharmaceutical composition described in any one of the above.

[0035] 17. The surfactant is 5 μg / mL to 5000 μg / mL, preferably 25 μg / mL mL to 2000 μg / mL, more preferably 50 μg / mL to 1000 μg / mL 17. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition is present in a concentration as specified in embodiment 16.

[0036] 18. The method of embodiment 17, wherein the surfactant is present in a concentration of 100 μg / mL. Pharmaceutical compositions.

[0037] 19. (a) Below: (ai) radionuclide 177 Lutetium (Lu-177) and (aii) Formula (I): [ka] with NeoB and the complex formed by; (b) gentisic acid or its salts and ascorbic acid or its salts; (c) optionally, macrogol 15 hydroxystearate; and (d) optionally, at least one other pharmaceutically acceptable excipient. Finished product.

[0038] 20. At least one other pharmaceutically acceptable excipient is a buffer, and / or a solvent, and / or pH adjusting agents.

[0039] 21. The buffer is selected from acetate buffer, citrate buffer, and phosphate buffer, preferably 21. The pharmaceutical composition of embodiment 20, wherein the buffer is selected from acetate buffers.

[0040] 22. The pharmaceutical composition according to embodiment 20 or 21, wherein the solvent is water for injection.

[0041] 23. The pharmaceutical composition according to embodiment 20, 21, or 22, wherein the pH adjuster is NaOH. Finished product.

[0042] twenty four. (a) Below: (ai) radionuclide 177 Lutetium (Lu-177) and (aii) Formula (I): [ka] with NeoB and the complex formed by; (b) gentisic acid or its salts and ascorbic acid or its salts; (c) macrogol 15 hydroxystearate and; (d) acetate buffer; (e) Water for injection; (f) NaOH; (g) DTPA, and a pharmaceutical composition comprising the same.

[0043] 25. The pharmaceutical composition according to any one of embodiments 1 to 24, wherein the pharmaceutical composition is an aqueous solution. Finished product.

[0044] 26. The pharmaceutical composition according to any one of embodiments 1 to 25, wherein the pharmaceutical composition is an infusion solution. Pharmaceutical composition.

[0045] 27. A compound according to any one of embodiments 1 to 3 for use in the treatment or prevention of cancer, typically GRPR-positive cancer. 26. A pharmaceutical composition according to any one of claims 1 to 26.

[0046] 28. The solution is produced in a commercial scale, particularly in batches of at least 0.5 Ci. 28. The pharmaceutical composition according to any one of embodiments 1 to 27, produced in size.

[0047] 29. A pharmaceutical composition according to any one of embodiments 1 to 28, which is for commercial use.

[0048] 30. A process for producing the pharmaceutical composition as defined above, comprising: (1) Radionuclide and GRP receptor peptide antagonist conjugate linked to a chelator The complex with the moiety, (1.1) A radionuclide and one stable compound, which is gentisic acid or its salt, against radiolysis. preparing an aqueous solution containing only the agent; (1.2) A GRP receptor peptide antagonist binding moiety linked to a chelator and any optionally, a surfactant; and preparing an aqueous solution comprising (1.3) Mix the solutions obtained in steps (1.1) and (1.2) and add the resulting mixture. heating and optionally filtering the resulting solution; and forming a process step by; (2) The complex solution obtained in step (1) (2.1) Optionally containing only one stabilizer against radiolysis, which is ascorbic acid Preparing a dilute aqueous solution; and (2.2.) The complex solution obtained in step (1) was mixed with the diluted solution obtained in step (2.1). Mix with the liquid to obtain the final solution; and a process step of diluting by

[0049] 31. The solution from step (1.1) is 177 LuCl3 and HCl 31. The process of embodiment 30, comprising:

[0050] 32. The solution prepared in step (1.1) is one of gentisic acid or its salts. Stabilizer alone should be added at least 1000 μg / mL, e.g., 1000 μg / mL to 1500 μg / mL. 32. The process of any one of embodiments 30-31, comprising at a concentration of 100 mg / mL.

[0051] 33. The solution of step (1.1) further comprises a buffer, preferably an acetate buffer. The process according to any one of embodiments 30 to 32.

[0052] 34. GRP receptor peptide linked to a chelator in the solution of step (1.2). Any of embodiments 30-33, wherein the antagonist-binding moiety is NeoB of formula (I): The process described in one. [ka]

[0053] 35. The solution in step (1.2) is macrogol 15-hydroxystearate. 35. The process of any one of embodiments 30 to 34, further comprising a surfactant.

[0054] 36. The solution prepared in step (2.1) is one containing ascorbic acid or its salt. Only the stabilizer is added at a concentration of at least 10,000 μg / mL, preferably at least 12,000 μg / mL. g / mL, preferably at least 15000 μg / mL, for example 12000 to 18000 36. The process of any one of embodiments 30 to 35, comprising at a concentration of 0.1 μg / mL.

[0055] 37. The solution in step (1.2) contains macrogol 15-hydroxystearate, 5 μg / mL to 5000 μg / mL, preferably 25 μg / mL to 2000 μg / mL, more preferably More preferably, the concentration is comprised between 50 μg / mL and 1000 μg / mL, and even more preferably 37. The method of claim 36, further comprising administering to said patient a therapeutically effective amount of at least 100 μg / L of hydroxybenzoates or ... Seth.

[0056] 38. In step (1.3), the resulting mixture is stirred for 1 to 59 minutes, preferably 2 30. Heating to a temperature of 70-99°C, preferably 90-98°C, for 15 minutes. 37. The process according to any one of claims 1 to 37.

[0057] 39. The complex obtained at the end of step (1.3) is further filtered at 0.20 μm. 39. The process according to any one of embodiments 30 to 38.

[0058] 40. The solution in step (2.1) is diethylenetriaminepentaacetic acid (DTPA) or its derivatives. 40. The process of any one of embodiments 30 to 39, further comprising a sequestering agent which is a salt of Process.

[0059] 41. An embodiment in which the solution of step (2.1) further comprises a pH adjuster that is NaOH. 30-40. The process according to any one of claims 30 to 40.

[0060] 42. Any of embodiments 30 to 41, wherein the solution of step (2.1) further comprises water for injection. The process described in any one of

[0061] 43. The process according to any one of embodiments 30 to 42, wherein (3) a process step of sterile filtering the solution obtained in step (2); (4) A process step of aseptically dispensing the filtered solution obtained in step (3) into unit-dose containers. and wherein the radionuclide is at least 370MBq / mL (at EOP) ± 3 Process steps present at concentrations resulting in a volumetric activity of 7MBq / mL (±10%) The process further comprises:

[0062] 44. The dose unit container in step (4) is a stoppered vial sealed within a lead container. 44. The process according to any one of embodiments 30 to 43.

[0063] 45. Obtained by the process defined in any one of embodiments 30 to 44. , pharmaceutical aqueous solutions. DETAILED DESCRIPTION OF THE INVENTION

[0064] definition In the following, the meanings of terms used in this specification are defined.

[0065] The term "about" or "approximately" is used herein to mean that the following value is within ±20%, preferably ± 10%, more preferably ±5%, even more preferably ±2%, even more preferably ±1% It means that it can change.

[0066] Unless otherwise defined, "%" herein refers to weight percent (wt%). and is also referred to as weight / weight percent (w / w%).

[0067] "Total concentration": the sum of one or more individual concentrations.

[0068] "Aqueous solution": a solution of one or more solutes in water.

[0069] "(ai) a radionuclide and (aii) a cell receptor-binding organic moiety linked to a chelating agent. and a complex formed by: a radionuclide metal ion is formed by a complex formed by a compound such as an amine or a carboxylic acid. It forms a non-covalent bond with the functional group of the chelating agent. The chelating agent can form a chelate complex. The complexing functional group has at least two such functional groups so that the complexing functional group can be

[0070] "Buffer solution of pH 4 to 6.0": acetate buffer solution, citrate buffer solution (e.g., citrate +HCl or citric acid + disodium hydrogen phosphate), or phosphate buffer (e.g., sodium dihydrogen phosphate + disodium hydrogen phosphate), and preferably the above buffer solution is an acetate buffer, preferably the acetate buffer is composed of acetic acid and sodium acetate. will be done.

[0071] "Sequestering agents", chelating agents suitable for complexing radionuclide metal ions, preferably or DTPA: diethylenetriaminepentaacetic acid.

[0072] "pH adjuster" is a substance that adjusts the pH value of a solution, thereby achieving the desired performance. It is a chemical substance added to the solution. pH control is achieved by adding pH adjusters to the formulation. Examples of pH adjusters include commonly used acids and bases, buffers, and the like. Examples of bases that can be used include buffer solutions, as well as mixtures of acids and bases. , NaOH, KOH, Ca(OH)2), sodium bicarbonate, potassium carbonate, and sodium carbonate Examples of acids that can be used include hydrochloric acid, acetic acid, citric acid, formic acid, fumaric acid, and thorium. Acids and sulfamic acids are preferred. Preferably, the pH adjuster is a base. More preferably, it is NaOH. The pH range of the fluid may be any suitable range, such as from about 2 to about 14. It can be a range.

[0073] "Commercial": A pharmaceutical product, e.g., a pharmaceutical solution, is approved by a health authority (e.g., the U.S. FDA or EMEA) A) to obtain marketing authorization in accordance with the quality and stability requirements of the drug as required by such health authorities. It is a pharmaceutical product that can be obtained (preferably obtained) by satisfying all of the above conditions. can be (and preferably is) manufactured on a commercial scale from or at a product production site, and subsequently are subject to controlled testing procedures and are available to end users in remote locations (e.g., hospitals or patient It is something that can be supplied (preferably supplied) to a person (a person who is a ...

[0074] Chelants relevant to the present disclosure include: DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DTPA: diethylenetriaminepentaacetic acid; NTA: nitrilotriacetic acid; EDTA: ethylenediaminetetraacetic acid; DO3A: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid; Trizoxetan, Tetraxetane Or it may be a mixture thereof, preferably DOTA.

[0075] "Cell receptor binding moiety": a chemical molecule that binds, at least in part, to a receptor molecule on the surface of a cell. A particularly suitable cell receptor binding moiety for the present disclosure is a somatostatin receptor binding peptide. Preferably, the somatostatin receptor binding peptide is octreotide, octreotide, Tate, lanreotide, vapreotide, pasireotide, iratreotide, pentetreotide octreotide, depreotide, satreotide, veldreotide, preferably octreotide. The compound is selected from octreotate and octreotate.

[0076] "Linked": The cell receptor-binding organic moiety is either directly linked to a chelator or to a phosphorus The linking bond is either connected via a car molecule, or preferably directly. is a covalent or non-covalent bond between the cell receptor binding organic moiety (and linker) and the chelator. The bond may be either a covalent bond, preferably a covalent bond.

[0077] "Radiolytic stabilizer": a stabilizer that protects organic molecules from radiolytic degradation, e.g. Gamma rays emitted from radionuclides break the bonds between atoms in organic molecules, forming radicals. When these radicals are released, they may then be undesirable or ineffective. or that the radicals undergo some other chemical reaction that may result in molecules that are even toxic. Therefore, these stabilizers are "free radicals." They are also called "radical scavengers" or for short "radical scavengers." Another term for these stabilizers is: "Radiation stability enhancers," "radiolysis stabilizers," or simply "quenchers."

[0078] "Radiochemical purity": The stated radioactivity present in the stated chemical or biological form. The percentage of nuclides. HPLC method or instant thin layer chromatography method ( Radiochromatographic methods such as iTLC are used in nuclear pharmacology to determine radiochemical purity. This is the most commonly accepted method for

[0079] As used herein, the terms "effective amount" or "therapeutically effective amount" of a compound refer to elicit a biological or medical response in the animal, e.g., to improve symptoms or alleviate the condition or the amount of compound that slows or retards the progression of the disease or prevents the disease. Refers to...

[0080] As used herein, the terms "substituted" or "optionally substituted" The term ranges from zero to the total number of open valences on the aromatic ring system. Number of halogens, -OR', -NR'R'', -SR', -SiR'R''R''', - OC(O)R', -C(O)R', -CO2R', -C(O)NR'R'', -OC(O )NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -N R''C(O)OR', -NR-C(NR'R''R''')=NR'''', -NR- C(NR'R'')=NR'''-S(O)R', -S(O)2R', -S(O)2NR 'R'', -NRSO2R', -CN, -NO2, -R', -N3, -CH(Ph)2, Fluoro(C1-C4)alkoxo and fluoro(C1-C4)alkyl (wherein R' , R'', R''', and R'''' are hydrogen, alkyl, heteroalkyl, cycloalkyl, and aryl, heteroaryl, and aryl groups independently selected from alkyl, heterocycloalkyl, aryl, and heteroaryl. The compounds of the present disclosure are optionally substituted with one or more substituents selected from the group consisting of: When contains more than one R group, for example, each of the R groups may be present in more than one of these groups. In the case where R', R'', R''', and R'''' are independently selected groups, can be.

[0081] As used herein, the term "alkyl" by itself or as another substituent As part of the alkyl group, it refers to a straight or branched chain alkyl functional group having 1 to 12 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, pentyl and its isomers (e.g., n-pentyl, pentyl, isopentyl), and hexyl and its isomers (e.g., n-hexyl, isopentyl, hexyl).

[0082] As used herein, the term "heteroaryl" refers to a heteroaryl containing 5 to 10 atoms. Polyunsaturated aromatic rings having a single ring or multiple aromatic rings fused or covalently bonded together refers to a ring system in which at least one ring is aromatic and at least one ring atom is N The heteroatoms are selected from nitrogen, oxygen, and sulfur. The nitrogen heteroatom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Such rings may be fused to an aryl ring, a cycloalkyl ring, or a heterocyclyl ring. Non-limiting examples of such heteroaryls include furanyl, thiophenyl, pyrrolidinyl, and the like. pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl Azolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxato thiatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, Oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl , benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl , indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiazolyl quinolinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl Examples include:

[0083] As used herein, the term "aryl" refers to an aryl group containing 6 to 10 ring atoms. a polyunsaturated aromatic hydrocarbyl group having a single ring or multiple aromatic rings fused together, where at least one ring is aromatic. An aromatic ring has one to two fused rings. an additional ring (cycloalkyl, heterocyclyl, or heterocyclic as defined herein) of Suitable aryl groups include benzopyranyl, Heterocyclyl-fused groups such as benzodioxolyl, benzodioxanyl, and the like Examples include phenyl, naphthyl, and phenyl rings.

[0084] As used herein, the term "halogen" includes fluoro (-F) groups, chloro (-C) groups, (-Cl), bromo (-Br), or iodo (-I) groups.

[0085] As used herein, the term "optionally substituted aliphatic chain" refers to a chain of 4 to 12 alkyl groups. Optionally substituted alkyl groups having 36 carbon atoms, preferably 12 to 24 carbon atoms. refers to an aliphatic chain.

[0086] The present disclosure is further described and exemplified below.

[0087] As used herein, the term "ratio between gentisic acid and ascorbic acid" is the free acid concentration ratio (μg / mL:μg / mL), i.e., the ratio of GA and AA as free acids. The concentration of counter ions such as sodium (Na) is not included in the calculation.

[0088] In general, the present disclosure relates to pharmaceutical compositions, particularly radiopharmaceutical compositions. For intravenous (IV) use / application / administration. The solution is stable, concentrated and ready to use. It is available.

[0089] A radiopharmaceutical composition according to the present disclosure comprises: (a) Below: (ai) a radionuclide; (aii) a GRP receptor peptide antagonist binding moiety linked to a chelator; and The complex formed thereby; (b) at least two stabilizers against radiolysis; (c) optionally a surfactant.

[0090] Radiolabeled GRPR antagonist The complex has the formula: MC-SP [In the formula, M is a radionuclide suitable for nuclear medicine, C is a chelator that binds to M; S is an optional spacer covalently attached between C and the N-terminus of P; P is a GRP receptor peptide antagonist, preferably having the general formula: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z (Xaa1 is absent or is selected from the amino acid residues Asn, Thr, Phe, 3-(2-thiazol-2-yl)-2-methyl-2-propanol, 2-amino ... Thi, 4-chlorophenylalanine (Cpa), α-naphthyl alanine Alanine (α-Nal), β-naphthylalanine (β-Nal), 1,2,3,4-tetrahydroalanine Hydronorharman-3-carboxylic acid (Tpi), Tyr, 3-iodo-tyrosine (o- I-Tyr), Trp, and pentafluorophenylalanine (5-F-Phe) (all as the L- or D-isomer; Xaa2 is Gln, Asn, or His; Xaa3 is Trp or 1,2,3,4-tetrahydronorharman-3-carboxylic acid ( Tpi); Xaa4 is Ala, Ser, or Val; Xaa5 is Val, Ser, or Thr; Xaa6 is Gly, sarcosine (Sar), D-Ala, or β-Ala; Xaa7 is His or (3-methyl)histidine (3-Me)His; Z is -NHOH, -NHNH2, -NH-alkyl, -N(alkyl)2, and -O- alkyl; or Z is [ka] where X is NH (amide) or O (ester), and R1 and R2 are the same. or different, and may contain a proton, an optionally substituted alkyl, an optionally substituted Alkyl ether, aryl, aryl ether, or alkyl-, halogen, hydroxy silyl, hydroxyalkyl, amine, amino, amido, or amide amide) substituted aryl or heteroaryl groups) That is why.

[0091] According to one embodiment, Z is selected from one of the following formulae, where X is NH or is O): [ka]

[0092] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-H is-Z; wherein Z is as defined above.

[0093] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-H is-Z; Z is Leu-Ψ(CHN)-Pro-NH and NH-CH(CH-CH(CH )2)2 is selected from, or Z is [ka] where X is NH (amide) and R2 is (CH2-CH(CH3)2 and R1 is the same as or different from R2 and is (CH2N)-Pro-NH2).

[0094] According to one embodiment, the chelator C is one chelate selected from the list below: obtained by grafting the agent: [ka]

[0095] According to one embodiment, M is 111 In, 18 F, 211 At, 82 Rb, 123 I, 131 I, 133 mIn, 99mTc, 94 mTc, 67 Ga, 66 Ga, 68 Ga, 5 2 Fe, 169 Er, 72 As, 97 Ru, 203 Pb, 212 Pb, 62 Cu, 64 C u, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52 mmn, 15 7 Gd, 177 Lu, 161 Tb, 69 Yb, 175 Yb, 105 Rh, 166 Dy, 1 66 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117 mS n, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 89 Zr, 225 Ac, 43 Sc, 44 Sc, and 47 Suitable for nuclear medicine, selected from Sc Preferably, M is a radionuclide. 111 In, 177 Lu, 225 Ac, and 68 Ga.

[0096] According to one embodiment, the chelator C is selected from the group consisting of DOTA, DTPA, NTA, EDTA, DO It is selected from the group consisting of 3A, NOC, and NOTA, and preferably DOTA.

[0097] According to one embodiment, S is a) Formula: [ka] where PABA is p-aminobenzoic acid and PABZA is p-aminobenzoic acid. PDA is a phenylenediamine, and PAMBZA is an aminobenzylamine. (methyl)benzylamine); b) a dicarboxylic acid, an ω-aminocarboxylic acid, an ω-diaminocarboxylic acid, or a compound of the formula: [ka] diamines of the formula (where DIG is diglycolic acid and IDA is iminodiacetic acid); c) PEG spacers of various chain lengths, especially PEG spacer sele [ka] d) α- and β-amino acids in single chains or homologous chains of various lengths or heterologous chains of various lengths; In particular: [ka] GRP(1-18), GRP(14-18), GRP(13-18), BBN(l-5 ), or [Tyr4]BB(1-5); or e) a combination of a, b, c, and d.

[0098] According to one embodiment, the GRPR antagonist has the following formula: [ka] wherein MC and P are as defined above. do.

[0099] According to one embodiment, P is DPhe-Gln-Trp-Ala-Val-Gly-H is-NH-CH(CH2-CH(CH3)2)2.

[0100] According to one embodiment, the complex has formula (I): [ka] NeoB1 ((DOTA-(p-aminobenzylamine-diglycolic acid)-[DP he-Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH( CH3)2]2).

[0101] According to one embodiment, the complex has the formula (II): [ka] Radiolabeled M-NeoB1 ((M-DOTA-(p-aminobenzylamine-diglycopolymer) D-Phe-Gln-Trp-Ala-Val-Gly-His-NH-C H[CH2-CH(CH3)2]2; wherein M is a radionuclide, preferably M is 177 Lu, 68 Ga and 111 In or (selected from the above).

[0102] According to one embodiment, the radiolabeled GRPR antagonist has formula (III): [ka] Radiolabeled NeoB2 ((M-N4(p-aminobenzylamine-diglycolic acid)- [D-Phe-Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2 -CH(CH3)2]2; where M is a radionuclide.

[0103] In one embodiment, M is 111 In, 133 mIn, 99 mTc, 94 mTc, 67 G a, 66 Ga, 68 Ga, 52 Fe, 169 Er, 72 As, 97 Ru, 203 Pb, 2 12 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52 mmn, 157 Gd, 177 Lu, 161 Tb, 69 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 T m, 121 Sn, 117 mSn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 1 98 Au, 199Au, 89 Zr, 225 Ac, and 47 A radionuclides may be selected from Sc Preferably, M is a species 111 In, 177 Lu, 225 Ac, and 68 From Ga be selected.

[0104] According to one embodiment, M is 177 In this case, the radiolabeled GRPR anta The agonist may be used in radionuclide therapy. According to another embodiment, M is 68 In Ga In this case, a radiolabeled GRPR antagonist can be used for PET. According to an embodiment, M is 111 In this case, the radiolabeled GRPR antagonist The device can be used for SPECT.

[0105] According to another particular embodiment, the GRPR antagonist has the following formula (IV): [ka] ProBOMB1 (DOTA-pABzA-DIG-D-Phe-Gln-Trp-A la-Val-Gly-His-Leu-Ψ(CH2N)-Pro-NH2).

[0106] Synthesis of Compounds of Formulas (I), (II), (III), and (IV) The compounds of formula (I), (II), (III) and (IV) are described in the reference "Positro n Emission Tomography Imaging of the Gas trin-Releasing Peptide Receptor with a N ovel Bombesin Analogue” ACS Omega 2019,4 , 1470-1478.

[0107] Pharmaceutical Composition Radiolabeled GRPR antagonists tend to degrade over time, eventually resulting in target release. At the end of the shelf life (72 hours), the radiochemical purity falls below the specification. This is problematic for the formulation of solutions that have been confirmed by the use of stabilizers against radiolysis. Stability.

[0108] As used herein, a "radiolytic stabilizer" refers to a compound that protects organic compounds from radiolysis. For example, gamma rays emitted from radionuclides are used to stabilize organic molecules. When the bond between the molecules is broken and radicals are formed, those radicals then react with the desired Anything that could result in molecules that are ineffective, potentially ineffective, or even toxic. The radicals are trapped by stabilizers that prevent them from undergoing other chemical reactions. Therefore, these stabilizers are also called "free radical scavengers" or "radical scavengers" for short. Other terms for these stabilizers are "radiation stabilization enhancers," "radiolytic stabilizers," or is simply a "quencher."

[0109] Generally, the stabilizer used in accordance with the present invention is gentisic acid (2,5-dihydroxybenzoic acid). ascorbic acid (L-ascorbic acid, vitamin C) or its salts ( For example, sodium ascorbate), methionine, histidine, melatonin, ethanol The preferred stabilizer may be selected from gentisic acid or its derivatives. salts and ascorbic acid or salts thereof.

[0110] Ethanol, when present in high concentrations, is often undesirable due to its associated tolerance issues. Ethanol in the solutions of the present disclosure is ideally should be avoided (in other words, ethanol-free), and at least the solution of the present disclosure The amount of ethanol in the final solution to be injected / infused should be, for example, less than 5%, preferably less than 2%. %, more preferably less than 1%. Even more preferably, the solution Does not contain ethanol.

[0111] In a first aspect, the present disclosure provides a method for treating a rheumatoid arthritis, comprising administering to a subject a radiolabeled GRPR antagonist as described herein; and at least two stabilizers against radiolysis. In one embodiment, the at least two stabilizers are gentisic acid (2,5-dihydroxybenzoic acid). Benzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g., sodium ascorbate), methionine, histidine, melatonin, ethanol and Se-methionine, preferably gentisic acid or a salt thereof and acetone. The at least two stabilizers may be selected from gentisin and sucralose, and ... The hydroxybenzoate may be selected from the group consisting of an acid or a salt thereof and ascorbic acid or a salt thereof.

[0112] In particular, the present inventors have incorporated radiolabeled GRPR antagonist compounds into pharmaceutical compositions. By adding specific amounts of both benzoic acid and gentisic acid, the It has been unexpectedly discovered that the radiochemical purity of the composition can exceed 95%.

[0113] In one embodiment, the ratio between gentisic acid and ascorbic acid is 1:16 to 1:10, Typically it is 1:15 to 1:10, for example 1:12 to 1:11.

[0114] In one embodiment, the gentisic acid or salt thereof is at least 1000 μg / mL, e.g. For example, it may be present at a concentration of 1000 μg / mL to 1500 μg / mL.

[0115] In one embodiment, the ascorbic acid or salt thereof is at least 10,000 μg / mL , preferably at least 12000 μg / mL, preferably at least 15000 μg / mL mL, for example, at a concentration of 12000 to 18000 μg / mL.

[0116] In one embodiment, the gentisic acid or salt thereof is at least 1000 μg / mL, for example 1 000μg / mL to 1500μg / mL, and ascorbic acid or a salt thereof is It is present at a concentration of 15000 μg / mL, for example 12000 to 18000 μg / mL.

[0117] In one embodiment, the radiopharmaceutical composition contains gentisic acid and ascorbic acid as radiation stabilizers. Both acetic acid and benzoic acid were present in the 1312 μg / mL and 15000 μg / mL concentrations, respectively.

[0118] In one embodiment, the pharmaceutical composition remains viable for up to 72 hours, more than 95%, preferably up to 72 hours. , with a radiochemical purity of greater than 98%.

[0119] GRPR antagonists bind to glass and plastic by nonspecific binding (NSB). They have a tendency to adhere to surfaces, which is problematic for formulating pharmaceutical compositions.

[0120] In a second aspect, the present disclosure provides a method for treating a rheumatoid arthritis, comprising administering to a subject a radiolabeled GRPR antagonist as described herein; A pharmaceutical composition comprising at least two stabilizers against radiolysis and optionally a surfactant. Related to products.

[0121] The surfactant comprises (i) a polyethylene glycol chain, (ii) a fatty acid ester, and In one embodiment, the surfactant may also include a compound having free ethylene glycol Includes

[0122] In one embodiment, the surfactant has the formula (V): [ka] (wherein n is an integer of 3 to 1000, preferably 5 to 500, more preferably 10 to 50) R, R is a fatty acid chain, preferably an optionally substituted aliphatic chain).

[0123] In one embodiment, the surfactant is polyethylene glycol 15-hydroxystearyl Contains ethylene glycol and free ethylene glycol.

[0124] In one embodiment, the surfactant is a non-ionic surfactant. The nonionic surfactant is macrogol 15 hydroxystearate (Kollipho r HS 15), poloxamer (Kolliphor P188), polysorbate 2 0 (Tween 20), polysorbate 80 (Tween 80), or an average molecular weight of 10 ,000 polyvinylpyrrolidone (polyvinylpyrrolidone K10). Alternatively, the nonionic surfactant may be macrogol 15-hydroxystearate (Ko lliphor HS 15).

[0125] Radiolabeled GRPR antagonist was 370MBq / mL (at EOP) ± 37MB q / mL (±10%).

[0126] The surfactant should be at least 5 μg / mL, preferably at least 25 μg / mL, more preferably Preferably, the surfactant is present at a concentration of at least 50 μg / mL. to 5000 μg / mL, preferably 25 μg / mL to 2000 μg / mL, more preferably The surfactant may be present in a concentration comprised between 50 μg / mL and 1000 μg / mL. It may be present at a concentration of 100 μg / mL.

[0127] In a third aspect, the present disclosure provides a method for treating a rheumatoid arthritis, comprising administering to a subject a radiolabeled GRPR antagonist as described herein; at least two stabilizers against radiolysis, optionally a surfactant, and at least and one other pharmaceutically acceptable excipient.

[0128] The pharmaceutically acceptable excipients may be any conventionally used ones, and may be selected from those having solubility and activity. The polymer is limited only by physicochemical considerations such as lack of reactivity with reactive compounds.

[0129] In particular, the one or more excipients are selected from buffers, and / or solvents, and / or pH adjusters. It can be done.

[0130] Buffers include acetate buffers, citrate buffers, and phosphate buffers. In an embodiment, the buffer is an acetate buffer.

[0131] In one embodiment, the solvent is water for injection.

[0132] In one embodiment, the pH adjuster is NaOH.

[0133] In a fourth aspect, the present disclosure provides a compound comprising the radionuclide lutetium-177 (Lu-177) and a compound of formula (I ): [ka] NeoB (DOTA-(p-aminobenzylamine-diglycolic acid)-[D-Phe -Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH(CH 3)2]2) and the complex formed by Gentisic acid or its salt and ascorbic acid or its salt, and macrogol 15 hydroxy A pharmaceutical composition comprising stearate, acetate buffer, water for injection, and NaOH. do.

[0134] According to one embodiment, the pharmaceutical composition is an aqueous solution, such as an injectable formulation. According to the form, the pharmaceutical composition is a solution for injection.

[0135] The requirements for an effective pharmaceutical carrier for an injectable composition are well known to those skilled in the art (e.g., Pha rmaceutics and Pharmacy Practice,JBLip pincott Company,Philadelphia,PA,Banker a nd Chalmers, eds., pages 238-250 (1982), and ^ SHP Handbook on Injectable Drugs,Trissel , 15th ed., pages 622-630 (2009).

[0136] The present disclosure also provides the above-mentioned compounds for use in treating or preventing cancer, typically GRPR-positive cancer. It relates to pharmaceutical compositions.

[0137] As used herein, the term "cancer" refers to a cancer that is autonomously growing (i.e., rapidly growing) refers to cells that have the capacity for hyperproliferation (an abnormal state or condition characterized by cell proliferation). and neoplastic conditions are considered pathological (i.e., characterizing or constituting the condition). or non-pathological (i.e., deviations from normal but not associated with pathology) This term is used regardless of histopathological type or stage of invasiveness. All types of cancerous growths or oncogenic processes, metastatic tissues or malignant cells, tissues, or organs.

[0138] In certain embodiments, the cancer is a prostate cancer, a breast cancer, or a tumor that exhibits neoplasia-associated vasculature that is GRPR. Cancer, small cell lung cancer, colon cancer, gastrointestinal stromal tumor, gastrinoma, renal cell carcinoma, gastrointestinal and pancreatic nerve Endocrine tumors, esophageal squamous cell tumors, neuroblastoma, head and neck squamous cell carcinoma, ovarian tumors, and uterine tumors In one embodiment, the cancer is selected from endometrial tumors and pancreatic tumors. In one embodiment, the cancer is prostate cancer or breast cancer. do.

[0139] In another aspect of the invention, the pharmaceutical composition is produced in a commercial scale manufacturing, in particular comprising at least Produced in 0.5 Ci batch sizes.

[0140] In another aspect of the invention, the pharmaceutical composition is for commercial use.

[0141] In a further aspect, the present disclosure also provides a method for treating or preventing cancer in a subject in need thereof. Radiolabeled GRPR antagonists (typically 177 Lu-Ne oB), said pharmaceutical composition being as described in any of the preceding embodiments. It is formulated with radiation stabilizers such as those listed in the is administered to the subject in a therapeutically effective amount, typically with a radiochemical purity (RCP) of 9 or greater at the time of administration. More than 5%.

[0142] In certain embodiments, the subject is a mammal, such as, but not limited to, a rodent, dog, cat, or is a primate. In a preferred embodiment, the subject is a human.

[0143] In certain embodiments, a therapeutically effective amount of the composition is administered to the subject 2-8 times per treatment. It is given.

[0144] For example, radiolabeled GRPR antagonists (especially 177 Lu-NeoB) The pharmaceutical composition is administered intravenously in 2 to 8 cycles (2000 to 10000 MBq each). and typically delivers radiochemical purity (RCP) greater than 95% at the time of administration to human patients. can be treated.

[0145] In accordance with the present disclosure, the following embodiments are provided: 1. (a) Below: (ai) a radionuclide; (aii) a GRP receptor peptide antagonist binding moiety linked to a chelator; and The complex formed thereby; (b) at least two stabilizers against radiolysis; (c) optionally a surfactant.

[0146] 2. The radioactive nuclide is 111 In, 18 F, 211 At, 82 Rb, 123 I, 13 1 I, 133mIn, 99 mTc, 94 mTc, 67 Ga, 66 Ga, 68 Ga, 52 F e. 169 Er, 72 As, 97 Ru, 203 Pb, 212 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52 mmn, 157 G d. 177 Lu, 161 Tb, 69 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117 mSn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 89 Zr , 225 Ac, 43 Sc, 44 Sc, and 47 Sc according to embodiment 1. A pharmaceutical composition. Preferably, M is 111 In, 177 Lu, 225 Ac, and 68 Ga? More preferably, 177 This is Lu.

[0147] 3. The radionuclides are at least 370MBq / mL (at EOP) ± 37MBq / mL 10. The pharmaceutical composition of embodiment 1, present in a concentration that results in a volumetric radioactivity of 100 mL (±10%). thing.

[0148] 4. The chelating agent is DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA. .

[0149] 5. The GRP receptor peptide antagonist binding moiety linked to the chelator has the formula The pharmaceutical composition of embodiment 1, wherein the NeoB is (I). [ka]

[0150] 6. The at least two stabilizers are gentisic acid (2,5-dihydroxybenzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g., sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine, preferably gentisic acid or a salt thereof and ascorbic acid or a salt thereof.

[0151] 7. The at least two stabilizers are gentisic acid or a salt thereof and ascorbic acid or The pharmaceutical composition of embodiment 6, which is a salt thereof.

[0152] 8. The ratio between gentisic acid and ascorbic acid is 1:16 to 1:10, typically 1 8. The pharmaceutical composition according to embodiment 7, wherein the DMSO concentration is 1:15 to 1:10, for example 1:12 to 1:11.

[0153] 9. The gentisic acid or salt thereof is at least 1000 μg / mL, for example 1000 μg / 9. The pharmaceutical composition of embodiment 7 or 8, wherein the composition is present in a concentration of from 1000 μg / mL to 1500 μg / mL.

[0154] 10. The ascorbic acid or its salt is at least 10,000 μg / mL, preferably is at least 12000 μg / mL, preferably at least 15000 μg / mL, e.g. Any one of embodiments 7 to 9, wherein the compound is present in a concentration of, for example, 12,000 to 18,000 μg / mL. The pharmaceutical composition described in

[0155] 11. The gentisic acid or salt thereof is at least 1000 μg / mL, for example 1000 μg / mL to 1500μg / mL, and ascorbic acid or a salt thereof is present in a concentration of 15000 12000-18000 μg / mL, for example, in embodiments 7- 10. A pharmaceutical composition according to any one of claims 1 to 10.

[0156] 12. The pharmaceutical preparation has a solubility of more than 95% for up to 72 hours, preferably 98% for up to 72 hours. 12. The pharmaceutical composition according to any one of embodiments 1 to 11, having a radiochemical purity of greater than 1000 mg / kg.

[0157] 13. Any of embodiments 1 to 12, wherein the surfactant is a nonionic surfactant. 1. The pharmaceutical composition described in Item 1.

[0158] 14. The nonionic surfactant is macrogol 15 hydroxystearate, poly Polysorbate 20, polysorbate 80, or polysorbate with an average molecular weight of 10,000 14. The pharmaceutical composition of embodiment 13, wherein the compound is selected from polyvinylpyrrolidone.

[0159] 15. The nonionic surfactant is macrogol 15-hydroxystearate. , The pharmaceutical composition according to embodiment 14.

[0160] 16. The surfactant is at least 5 μg / mL, preferably at least 25 μg / mL 16. The method of claim 1, wherein the hydroxybenzoate is present in a concentration of at least 50 μg / mL, more preferably at least 50 μg / mL. The pharmaceutical composition described in any one of the above.

[0161] 17. The surfactant is 5 μg / mL to 5000 μg / mL, preferably 25 μg / mL mL to 2000 μg / mL, more preferably 50 μg / mL to 1000 μg / mL 17. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition is present in a concentration as specified in embodiment 16.

[0162] 18. The method of embodiment 17, wherein the surfactant is present in a concentration of 100 μg / mL. Pharmaceutical compositions.

[0163] 19. (b) Below: (ai) radionuclide 177 Lutetium (Lu-177) and (aii) Formula (I): [ka] with NeoB and the complex formed by; (b) gentisic acid or its salts and ascorbic acid or its salts; (c) optionally, macrogol 15 hydroxystearate; and (d) optionally, at least one other pharmaceutically acceptable excipient. Finished product.

[0164] 20. At least one other pharmaceutically acceptable excipient is a buffer, and / or a solvent, and / or pH adjusting agents.

[0165] 21. The buffer is selected from acetate buffer, citrate buffer, and phosphate buffer, preferably 21. The pharmaceutical composition of embodiment 20, wherein the buffer is selected from acetate buffers.

[0166] 22. The pharmaceutical composition according to embodiment 20 or 21, wherein the solvent is water for injection.

[0167] 23. The pharmaceutical composition according to embodiment 20, 21, or 22, wherein the pH adjuster is NaOH. Finished product.

[0168] twenty four. (a) Below: (ai) radionuclide 177 Lutetium (Lu-177) and (aii) Formula (I): [ka] with NeoB and the complex formed by; (b) gentisic acid or its salts and ascorbic acid or its salts; (c) macrogol 15 hydroxystearate and; (d) acetate buffer; (e) Water for injection; (f) NaOH; (g) DTPA, and a pharmaceutical composition comprising the same.

[0169] 25. The pharmaceutical composition according to any one of embodiments 1 to 24, wherein the pharmaceutical composition is an aqueous solution. Finished product.

[0170] 26. The pharmaceutical composition according to any one of embodiments 1 to 25, wherein the pharmaceutical composition is an infusion solution. Pharmaceutical composition.

[0171] 27. A compound according to any one of embodiments 1 to 3 for use in the treatment or prevention of cancer, typically GRPR-positive cancer. 26. A pharmaceutical composition according to any one of claims 1 to 26.

[0172] 28. The solution is produced in a commercial scale, particularly in batches of at least 0.5 Ci. 28. The pharmaceutical composition according to any one of embodiments 1 to 27, produced in size.

[0173] 29. A pharmaceutical composition according to any one of embodiments 1 to 28, which is for commercial use.

[0174] 30. A process for producing the pharmaceutical composition as defined above, comprising: (1) Radionuclide and GRP receptor peptide antagonist conjugate linked to a chelator The complex with the moiety, (1.1) A radionuclide and one stable compound, which is gentisic acid or its salt, against radiolysis. preparing an aqueous solution containing only the agent; (1.2) A GRP receptor peptide antagonist binding moiety linked to a chelator and any optionally, a surfactant; and preparing an aqueous solution comprising (1.3) Mix the solutions obtained in steps (1.1) and (1.2) and add the resulting mixture. and optionally filtering the resulting complex; and forming a process step by; (2) The complex solution obtained in step (1) (2.1) Optionally containing only one stabilizer against radiolysis, which is ascorbic acid Preparing a dilute aqueous solution; and (2.2.) The complex solution obtained in step (1) was mixed with the diluted solution obtained in step (2.1). Mix with the liquid to obtain the final solution; and a process step of diluting by

[0175] 31. The solution from step (1.1) is 177 LuCl3 and HCl 31. The process of embodiment 30, comprising:

[0176] 32. The solution prepared in step (1.1) is one of gentisic acid or its salts. Stabilizer alone should be added at least 1000 μg / mL, e.g., 1000 μg / mL to 1500 μg / mL. 32. The process of any one of embodiments 30-31, comprising at a concentration of 100 mg / mL.

[0177] 33. The solution of step (1.1) further comprises a buffer, preferably an acetate buffer. The process according to any one of embodiments 30 to 32.

[0178] 34. GRP receptor peptide linked to a chelator in the solution of step (1.2). Any of embodiments 30-33, wherein the antagonist-binding moiety is NeoB of formula (I): The process described in one. [ka]

[0179] 35. The solution in step (1.2) is macrogol 15-hydroxystearate. 35. The process of any one of embodiments 30 to 34, further comprising a surfactant.

[0180] 36. The solution prepared in step (2.1) is one containing ascorbic acid or its salt. Only the stabilizer is added at a concentration of at least 10,000 μg / mL, preferably at least 12,000 μg / mL. g / mL, preferably at least 15000 μg / mL, for example 12000 to 18000 36. The process of any one of embodiments 30 to 35, comprising at a concentration of 0.1 μg / mL.

[0181] 37. The solution in step (1.2) contains macrogol 15-hydroxystearate, 5 μg / mL to 5000 μg / mL, preferably 25 μg / mL to 2000 μg / mL, more preferably More preferably, the concentration is comprised between 50 μg / mL and 1000 μg / mL, and even more preferably 37. The method of claim 36, further comprising administering to said patient a therapeutically effective amount of at least 100 μg / L of hydroxybenzoates or ... Seth.

[0182] 38. In step (1.3), the resulting mixture is stirred for 1 to 59 minutes, preferably 2 30. Heating to a temperature of 70-99°C, preferably 90-98°C, for 15 minutes. 37. The process according to any one of claims 1 to 37.

[0183] 39. The complex obtained at the end of step (1.3) is further filtered at 0.20 μm. 39. The process according to any one of embodiments 30 to 38.

[0184] 40. The solution in step (2.1) is diethylenetriaminepentaacetic acid (DTPA) or its derivatives. 40. The process of any one of embodiments 30 to 39, further comprising a sequestering agent which is a salt of Process.

[0185] 41. An embodiment in which the solution of step (2.1) further comprises a pH adjuster that is NaOH. 30-40. The process according to any one of claims 30 to 40.

[0186] 42. Any of embodiments 30 to 41, wherein the solution of step (2.1) further comprises water for injection. The process described in any one of

[0187] 43. The process according to any one of embodiments 30 to 42, wherein (3) a process step of sterile filtering the solution obtained in step (2); (4) A process step of aseptically dispensing the filtered solution obtained in step (3) into unit-dose containers. and wherein the radionuclide is at least 370MBq / mL (at EOP) ± 3 Process steps present at concentrations resulting in a volumetric activity of 7MBq / mL (±10%) The process further comprises:

[0188] 44. The dose unit container in step (4) is a stoppered vial sealed within a lead container. 44. The process according to any one of embodiments 30 to 43.

[0189] 45. Obtained by the process defined in any one of embodiments 30 to 44. , pharmaceutical aqueous solutions. [Example]

[0190] The present disclosure will now be described in more detail, specifically with reference to examples. It is not intended to be limiting.

[0191] material: 177 LuCl3 can be obtained from commercial sources, e.g., IDB Holland BV. All other ingredients of the drug are commercially available from a variety of sources.

[0192] Methods for preparing pharmaceutical compositions The MiniAIO synthesis system allows for automated production of Lu-NeoB. The synthesis procedure was formulated as follows: 1. 177 Transfer LuCl3 into the reactor; 2. Transfer the reaction buffer to the reactor. The reaction buffer is a sodium acetate buffer and gentisic acid The acetate buffer can maintain the pH of the labeling at 4-5 and is suitable for gentamicin. The phosphate protects the peptide from radiolysis during the labeling step; 3. Add NeoB solution containing Kolliphor HS 15 to the reactor; 4. Heat at 95°C for 5 minutes; At the end of labeling, dilution solution is added to obtain a volumetric radioactivity of 10 mCi / mL. The dilution solution contained ascorbic acid (antioxidant), DTPA (sequestering agent), NaOH (p H adjuster), and water for injection.

[0193] Example 1: Effect of formulation on radiochemical purity of pharmaceuticals Contains the same amount of antioxidants as present in Lutathera formulations 177 Lu label generation Stability of the product over 72 hours. In particular, the following conditions are replicated: Gentisic acid 630 μg / mL is added before the labeling step; Kolliphor HS 15: 1 mg is added before the labeling step; ○ Peptide:Lu ratio ≥ 1.5; o Addition of 2795 μg / mL of ascorbic acid at the end of the reaction during the compounding step; ○Final volume radioactivity 10mCi / mL; ○Final pH 4~6; Reaction buffer: acetic acid / acetate buffer;

[0194] The MiniAIO synthesizer allows for both manual and automated radiolabeling testing. The synthesis procedure is formulated as follows: 1. 177 Transfer LuCl3 into the reactor; 2. Transfer the reaction buffer to the reactor. The reaction buffer is a sodium acetate buffer and gentisic acid The acetate buffer can maintain the pH of the labeling at 4-5 and is suitable for gentamicin. The phosphate protects the peptide from radiolysis during the labeling step; 3. Add NeoB1 solution containing Kolliphor HS 15 to the reactor; 4. Heat at 95°C for 5 minutes; At the end of labeling, dilution solution is added to obtain a volumetric radioactivity of 10 mCi / mL. The dilution solution contained ascorbic acid (antioxidant), DTPA (sequestering agent), NaOH (p H adjuster), and water for injection.

[0195] [Table 1]

[0196] As the results shown in Table 1 show, the product formulated under the same conditions as Lutathera was It gradually deteriorates over time, eventually falling below the standard at the end of the target shelf life (72 hours). As a result, the radiochemical purity is 177 The development of LuNeoB has simplified the labeling step A suitable amount of gentisic acid and The focus has been on the identification of ascorbic acid.

[0197] Example 2: Identification of suitable formulations to improve the radiochemical purity of pharmaceuticals Antioxidants / free radical scavengers such as ascorbic acid and gentisic acid typically It is used in the preparation of radiopharmaceuticals to protect the labeled molecule from radiolysis.

[0198] Therefore, to identify an appropriate formulation to improve radiochemical purity, The amount of benzoic acid or ascorbic acid was increased, and all other conditions, including the amount of other antioxidants, were kept constant. By keeping the temperature constant, different formulations are tested.

[0199] ·Change in the proportion of gentisic acid First, we investigate the effect of varying the proportion of gentisic acid. , we kept all other conditions, including the amount of ascorbic acid, constant. Test for increasing amounts of phosphate.

[0200] Different concentrations of gentisic acid were added up to 1000 μg / mL as shown in the table below. and test under the following conditions: Gentisic acid is added before the labeling step; Kolliphor HS 15: 1 mg is added before labeling; Add 2700 μg / mL of ascorbic acid at the end of labeling during the compounding step; ○Final volume radioactivity 10mCi / mL; ○ Peptide:Lu ratio ≥ 1.5; ○Final pH 4~6; Reaction buffer: acetic acid / acetate buffer;

[0201] [Table 2]

[0202] The results shown in Table 2 were obtained when the concentration of ascorbic acid was set at 2700 μg / mL and gentisingin If the maximum acid concentration is set at 1000 μg / mL, the radiochemical purity will be indicates that the product does not meet the standard.

[0203] Therefore, altering the proportion of gentisic acid does not affect the radiochemical purity.

[0204] -Change in the proportion of ascorbic acid We then investigated the effect of different amounts of ascorbic acid on the stability of the final product. As shown in the table below, different concentrations of ascorbic acid were administered up to 15,000 μg. / mL and tested under the following conditions: Gentisic acid 1000 μg / mL added before the labeling step; Kolliphor HS 15: 1 mg is added before labeling; Adding ascorbic acid at the end of labeling during the compounding step; ○Final volume radioactivity 10mCi / mL; ○ Peptide:Lu ratio ≥ 1.5; ○Final pH 4~6; Reaction buffer: acetic acid / acetate buffer;

[0205] [Table 3]

[0206] As shown by the results in Table 3, at least 1000 μg / mL of gentisic acid and 100 The radiochemical purity of the drug is up to Over 95% for 72 hours. Tests performed with increasing concentrations of ascorbic acid , showing a clear improvement in the stability of the product at 15000 μg / mL (at the end of the shelf life RCP% >98%).

[0207] Evaluation of the antioxidant properties of ascorbic acid by removing gentisic acid from liquid formulations Based on the results shown in Table 3, the minimum amount of ascorbic acid for these studies was 15,000 μg. As shown in Table 4, gentisic acid was not part of the formulation and was used as an antioxidant. Ascorbic acid is the only known ester of benzoyl esters. The following conditions apply: Kolliphor HS 15: 1 mg is added before labeling; Add 15000 μg / mL of ascorbic acid at the end of labeling during the compounding step; ○Final volume radioactivity 10mCi / mL; ○ Peptide:Lu ratio ≥ 1.5; ○Final pH 4~6; Reaction buffer: acetic acid / acetate buffer;

[0208] [Table 4]

[0209] As can be seen, in the absence of gentisic acid, the radiochemical purity of the drug after 72 hours was Therefore, based on the results of this experiment, the concentration of gentisic acid and ascorbic acid is less than 95%. Vicinal acid plays a complementary positive role in the stability of pharmaceuticals.

[0210] In conclusion, the best results regarding the radiochemical stability of the products were obtained with gentisic acid and ascorbic acid. The test contained both benzoyl peroxidase and benzoyl peroxidase at concentrations of 1000 μg / mL and 15000 μg / mL, respectively. It was obtained with the following formulation.

[0211] Example 3: Final formulation test at 200 mCi The following test was carried out by subjecting the formulation identified through the previous development tests (Examples 1 to 3) to 200 mCi It is designed to check the radiation level. Based on the above results, the amount of gentisic acid and ascorbic acid was increased to 1000 μg / The synthesis is carried out under the following conditions: 1000 μg / mL of gentisic acid is added to the reactor from the beginning; Add Kolliphor HS 15 to the peptide solution to a final concentration of 100 μg / to mL; Add 15,000 μg / mL of ascorbic acid at the end of the labeling step during the compounding step. ; Final volume radioactivity after compounding: 10 mCi / mL; ○ Peptide:Lu ratio ≥ 1.5; ○Final pH 4~6; Reaction buffer: acetic acid / acetate buffer;

[0212] Radiolabeling can be automated using the MiniAIO synthesizer. Formulated as follows: 1. 177 Transfer LuCl3 into the reactor; 2. Transfer the reaction buffer to the reactor. The reaction buffer is a sodium acetate buffer and gentisic acid The acetate buffer can maintain the pH of the labeling at 4-5 and is suitable for gentamicin. The phosphate protects the peptide from radiolysis during the labeling step; 3. Add NeoB1 solution containing Kolliphor HS 15 to the reactor; 4. Heat at 95°C for 5 minutes; 5. At the end of labeling, add dilution solution to obtain a volumetric radioactivity of 10 mCi / mL The diluted solution contains ascorbic acid (antioxidant), DTPA (sequestering agent), and NaOH. (pH adjuster), and saline solution.

[0213] As the results shown in Table 7 show, 1000 μg / mL gentisic acid and 15000 μg / mL ascorbic acid, for a radioactivity level of 200 mCi, 177 L The radiochemical purity of uNeoB is consistently well above 95% for up to 72 hours.

[0214] [Table 5]

[0215] Example 4: Final formulation test on 0.5 Ci batches Based on the results obtained during R&D lab-scale product development, the first scale-up The following composition was selected for the batch production: Gentisic acid 1000 μg / mL; Ascorbic acid 15000μg / mL; Kolliphor HS 15 100 μg / mL; ○Volumetric radioactivity 10 mCi / mL; ○Final pH 4.0~6.0; Reaction buffer: acetic acid / acetate buffer;

[0216] To transition from R&D compounding to pharmaceutical quality medicines, Gipharma produces Reaction buffer (product code F193) and formulation buffer used in the production of Lutathera Buffer solution (product code F191) was used to produce the scale-up batches. 177 Lu The stability of the NeoB final product was evaluated by three different sample volumes (4 mL, The doses were evaluated for up to 72 hours at doses of 6 mL and 25 mL.

[0217] To industrialize the production of the drug substance, scale-up tests were carried out under the support of an automated synthesis module. The aim was also to optimize the manufacturing process carried out in the synthesis module. , 177 A drug substance (mother liquor) containing the Lu-labeled molecule is prepared.

[0218] An automated synthesis process was developed to produce the radioactive drug substance as a sterile, concentrated aqueous mother liquor. GMP-compliant software for monitoring and recording process parameters. MiniAIO (TRAS), an automated and remotely controlled standalone closed system synthesis module The drug substance synthesis steps were set up in the synthesizer module.

[0219] Mini AIO radiosynthesis module is the first radiopharmaceutical industry This module has a disk that is preferred over fixed flow path devices. The disposable flow path is incorporated, which means that the disposable flow path is sterile and This is to ensure a halogen-free flow path and eliminate the possibility of cross-contamination between batches. The construction module is housed in a lead-shielded hot cell supplied with Grade C HEPA filtered air. The laboratory is placed in a clean, Grade C laboratory with an isolator.

[0220] Table 8 lists the target formulation properties selected for the production of a 0.5 Ci batch size.

[0221] [Table 6]

[0222] ○ 177 Theoretical activity of LuCl3 = 0.5 Ci; ○When synthesis begins 177 Specific activity of LuCl3 = 9.7 Ci / mg; ○Net amount of NeoB1 = 0.600 mg; ○ Molar ratio (NeoB1:Lu) = 1.300; Synthesis using MiniAIO module (Trasis); ○Labeling time: 5 minutes; ○Labeling temperature: 95℃;

[0223] 177 Some related compounds obtained during the production of LuNeoB1.0.5 Ci batch size The IPC results are listed in Table 9.

[0224] [Table 7]

[0225] To assess the effect of oxidative degradation, three sample volumes were dispensed at the end of production: · 25mL (vial-1); · 4mL (Vial-2, Vial-3, Vial-4); · 6mL (vial-5);

[0226] In sample vial 4, compound step was performed to obtain a final concentration of approximately 1.312 mg / mL. Addition of additional amounts of gentisic acid to the mixture ultimately further reduced radiolysis. Sample vial-3 was kept agitated throughout the stability study.

[0227] All samples were stored at 25±2° C. The various samples dispensed are shown in Table 10.

[0228] [Table 8]

[0229] Table 11 shows 177 Radiochemistry obtained with a scaled-up batch of LuNeoB1 0.5 Ci As can be seen, the radiochemical purity of the product at time t0 is , meeting the target specification of >97.00%.

[0230] Stability testing performed on Vial-1 (25 mL sample) showed very low solubility even after 72 hours. Although promising results were observed, Vial-2 (4 mL sample) and Vial-3 (4 mL sample) These (mixtures) exhibit radiochemical purity below 95.00% at the end of their intended shelf life. Preliminary results seem to indicate a negative effect of O2 on the stability of the final product. .

[0231] Addition of additional amounts of gentisic acid (sample vial-4) improved the stability of the final product. However, the target validity period was never successfully met. Finally, Vial-5 (6 mL sample) met the radiochemical purity specification at 72 hours. Despite not having a 4 mL sample volume, it showed improvements in terms of stability results. show.

[0232] [Table 9]

[0233] Final target formulation and composition details The final amounts of ascorbic acid and gentisic acid were determined based on data collected during development activities. In particular, gentisic acid at a concentration of 1312 ppm is Together with scorbic acid, it has shown excellent antioxidant properties that can achieve the target shelf life.

[0234] Based on all development tests performed, radioactivity levels up to 500 mCi 177 Lu The formulation chosen for the production of NeoB is as follows:

[0235] [Table 10]

Claims

1. (a) Below: (ai) a radionuclide; (aii) a gastrin-releasing peptide receptor peptide antagonist linked to a chelator. a complex formed by a hydroxyl group-binding moiety; (b) at least two stabilizers against radiolysis; (c) optionally a surfactant.

2. The radionuclide is １１１ In, １８ F. ２１１ At, ８２ Rb, １２３ I, １３１ I 、 １３３ mIn、 ９９ mTc、 ９４ mTc、 ６７ Ga、 ６６ Ga、 ６８ Ga、 ５２ Fe、 １６９ Er, ７２ As, ９７ Ru, ２０３ Pb, ２１２ Pb, ６２ Cu, ６４ Cu, ６７ C １８６ ee １８８ ee ８６ Y ９０ Y ５１ r、 ５２ mMn、 １５７ G １７７ u、 １６１ (b、) ６９ b、 １７５ b、 １０５ (2) １６６ y、 １６６ o 、 １５３ Sm、 １４９ Pm、 １５１ Pm、 １７２ Tm、 １２１ Sn、 １１７ mSn、 ２１ ３ Bi、 ２１２ Bi、 １４２ Pr、 １４３ Pr、 １９８ Au、 １９９ Au、 ８９ Zr、 ２ ２５ Ac, ４３ Sc, ４４ Sc, and ４７ Sc, preferably １１１ In, １ ７７ Lu, ２２５ Ac, and ６８ Ga, more preferably １７７ Lu, The pharmaceutical composition of claim 1.

3. The radionuclide is at least 370 MBq / mL (at the end of the process) ± 37 MBq 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is present at a concentration that results in a volumetric radioactivity of 100 mg / mL (±10%). thing.

4. The chelating agent is DOTA, DTPA, NTA, EDTA, DO3A, NOC, and 2. The pharmaceutical composition according to claim 1, wherein the compound is selected from NOTA, preferably DOTA.

5. a gastrin-releasing peptide receptor peptide antagonist bond linked to said chelator; 2. The pharmaceutical composition of claim 1, wherein the binding moiety is NeoB of formula (I). 【Chemistry 1】

6. The at least two stabilizers are gentisic acid or a salt thereof, ascorbic acid or a salt thereof , methionine, histidine, melatonin, ethanol, and Se-methionine, preferably is selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof. The pharmaceutical composition described above.

7. The at least two stabilizers are gentisic acid or a salt thereof and ascorbic acid or a salt thereof. The pharmaceutical composition of claim 6 , which is a salt.

8. The ratio between gentisic acid and ascorbic acid is 1:16 to 1:10, typically 1:1 8. The pharmaceutical composition of claim 7, wherein the ratio is 1:5 to 1:10, for example 1:12 to 1:

11.

9. The gentisic acid or salt thereof has a concentration of at least 1000 μg / mL, for example 1000 μg / mL 9. The pharmaceutical composition of claim 7 or 8, which is present in a concentration of up to 1500 μg / mL.

10. The ascorbic acid or salt thereof is at least 10,000 μg / mL, preferably at least at least 12000 μg / mL, preferably at least 15000 μg / mL, for example 12 10. The method according to claim 7, wherein the composition is present in a concentration of from 000 to 18,000 μg / mL. Pharmaceutical compositions.

11. The gentisic acid or salt thereof has a concentration of at least 1000 μg / mL, for example 1000 μg / mL 1500 μg / mL, and ascorbic acid or a salt thereof is present at a concentration of 15000 μg / mL.

11. The method of claim 7, wherein the compound is present in a concentration of 12,000 to 18,000 μg / mL, for example 12,000 to 18,000 μg / mL. The pharmaceutical composition described in any one of claims 1 to 4.

12. The pharmaceutical formulation has a release rate of more than 95% for up to 72 hours, preferably more than 98% for up to 72 hours. The pharmaceutical composition according to any one of claims 1 to 11, having radiochemical purity.

13. (c) Below: (ai) radioactive nuclide １７７ Lutetium (Lu-177), (aii) Formula (I): 【Chemistry 2】 and a complex formed by (b) gentisic acid or a salt thereof and ascorbic acid or a salt thereof; (c) optionally macrogol 15 hydroxystearate; and (d) optionally, at least one other pharmaceutically acceptable excipient. Finished product.

14. The at least one other pharmaceutically acceptable excipient may be a buffer, a solvent, and 14. The pharmaceutical composition according to claim 13, wherein the additive is selected from the group consisting of a hydroxybenzoate and / or a pH adjuster.

15. (a) Below: (ai) radioactive nuclide １７７ Lutetium (Lu-177), (aii) Formula (I): 【Transformation 3】 and a complex formed by (b) gentisic acid or a salt thereof and ascorbic acid or a salt thereof; (c) macrogol 15 hydroxystearate; (d) acetate buffer; (e) water for injection; (f) with NaOH; (g) DTPA.

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