WO2020021310A1 - Solutions complexes de radionucléides, stables, concentrées - Google Patents

Solutions complexes de radionucléides, stables, concentrées Download PDF

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Publication number
WO2020021310A1
WO2020021310A1 PCT/IB2018/055575 IB2018055575W WO2020021310A1 WO 2020021310 A1 WO2020021310 A1 WO 2020021310A1 IB 2018055575 W IB2018055575 W IB 2018055575W WO 2020021310 A1 WO2020021310 A1 WO 2020021310A1
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WO
WIPO (PCT)
Prior art keywords
stabilizer
aqueous solution
pharmaceutical aqueous
solution according
dota
Prior art date
Application number
PCT/IB2018/055575
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English (en)
Inventor
Giovanni TESORIERE
Maurizio Mariani
Lorenza Fugazza
Francesco DE PALO
Donato BARBATO
Daniela Chicco
Clementina BRAMBATI
Original Assignee
Advanced Accelerator Applications (Italy) Srl
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Advanced Accelerator Applications (Italy) Srl filed Critical Advanced Accelerator Applications (Italy) Srl
Priority to PCT/IB2018/055575 priority Critical patent/WO2020021310A1/fr
Priority to JP2021504214A priority patent/JP7358451B2/ja
Priority to PCT/IB2018/057415 priority patent/WO2020021322A1/fr
Priority to AU2018433575A priority patent/AU2018433575B2/en
Priority to BR112021001148-0A priority patent/BR112021001148A2/pt
Priority to KR1020247006883A priority patent/KR20240033296A/ko
Priority to CA3153630A priority patent/CA3153630A1/fr
Priority to CN201880095724.5A priority patent/CN112584875A/zh
Priority to EP18783136.7A priority patent/EP3826686A1/fr
Priority to US16/140,962 priority patent/US20200030466A1/en
Priority to MX2021000805A priority patent/MX2021000805A/es
Priority to SG11202100645XA priority patent/SG11202100645XA/en
Priority to DE202018006567.6U priority patent/DE202018006567U1/de
Priority to JP2021504167A priority patent/JP7402218B2/ja
Priority to KR1020217005212A priority patent/KR102643582B1/ko
Priority to US16/175,261 priority patent/US10596276B2/en
Priority to US16/175,239 priority patent/US10596278B2/en
Priority to TW108124451A priority patent/TW202019489A/zh
Priority to ARP190102070A priority patent/AR119655A1/es
Priority to EP19773177.1A priority patent/EP3826687A1/fr
Priority to US17/263,140 priority patent/US20220072166A1/en
Priority to JP2021504165A priority patent/JP2021531306A/ja
Priority to CN201980048954.0A priority patent/CN112955188A/zh
Priority to PCT/IB2019/056315 priority patent/WO2020021465A1/fr
Publication of WO2020021310A1 publication Critical patent/WO2020021310A1/fr
Priority to US16/827,606 priority patent/US11904027B2/en
Priority to IL280314A priority patent/IL280314A/en
Priority to CONC2021/0000506A priority patent/CO2021000506A2/es
Priority to US17/209,122 priority patent/US20210379213A1/en
Priority to AU2022203683A priority patent/AU2022203683B2/en
Priority to JP2023085193A priority patent/JP2023117417A/ja
Priority to JP2023085502A priority patent/JP2023126209A/ja
Priority to US18/494,042 priority patent/US20240075171A1/en
Priority to JP2023219738A priority patent/JP2024038132A/ja
Priority to AU2024201217A priority patent/AU2024201217A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to radionuclide complex solutions of high concentration and of high chemical and radiochemical stability, that allows their use as commercial drug product for diagnostic and/or therapeutic purposes.
  • the concept of targeted drug delivery is based on cell receptors which are overexpressed in the target cell in contrast to the not-to-be-targeted cells. If a drug has a binding site to those overexpressed cell receptors it allows the delivery the drug after its systemic administration in high concentration to those target cells while leaving other cells, which are not of interested, unaffected. For example, if tumor cells are characterized by an overexpression of a specific cell receptor, a drug with binding affinity to said receptor will after intravenous infusion accumulate in high concentration in the tumor tissue while leaving the normal tissue unaffected.
  • This targeted drug delivery concept has also been used in radiomedicine to deliver radionuclides selectively to the target cells for diagnostic or therapeutic purposes.
  • radiolysis the decay of the radionuclide occurs constantly, e.g. also during the manufacturing and during storage of the drug product, and the released high energy emissions induce the cleavage of the chemical bonds of the molecules which form part of the drug product.
  • the radiolytic degradation of the receptor binding moiety of the drug may lead to a decrease in its efficacy to act as a diagnostic and/or therapeutic.
  • the drug product may be stored at low temperatures, or produced in high dilution, or stabilizers may be added.
  • Adding stabilizers however may be problematic as those chemicals may have a negative impact on the complexation of the radionuclide into the chelating agent.
  • the present inventors have now found a way to design and produce a highly concentrated radionuclide complex solution which is chemically and radiochemically very stable even if stored at ambient or short term elevated temperatures.
  • the present invention is provided in various aspects as outlined in the following:
  • a pharmaceutical aqueous solution comprising
  • said radionuclide is present in a concentration that it provides a volumetric radioactivity of at least 100 MBq/mL, preferably of at least 250 MBq/mL.
  • Said stabilizer(s), component (b), is (are) present in a total concentration of at least 0.2 mg/ml_, preferably at least 0.5 mg/ml_, more preferably at least 1 .0 mg/ml_, even more preferably at least 2.7 mg/ml_.
  • a pharmaceutical aqueous solution comprising
  • the present invention provide the following advantages:
  • the high concentration allows administering a high dose within a short time frame.
  • the high dose of 7.4 GBq can be provided in a small volume of 20.5 to 25.0 mL which allows the IV infusion administration to be completed within about 20 to 30 minutes.
  • suitable stabilizer(s), according to the present invention as described, herein ensures high stability, at least 95%, 96%, 97%, 98%, 99% or 100% chemical stability with respect to the chemical purity for the cell receptor-binding molecule after 72 hours at 25 °C, even if this molecule is a sensitive peptide molecule.
  • DOTA-TATE 100% chemical purity were found after 72 hours at 25 °C and even after 48 hours at 32 °C were found. Even under short term elevated temperature conditions (32°C for 12 h and 25° for 60 h) such high stability was found with respect to radiochemical purity.
  • suitable stabilizer(s), according to the present invention as described, herein ensures high stability, at least 95% radiochemical stability with respect to the radiochemical purity radionuclide complex.
  • E.g. for 177 Lu-DOTA-TATE at least 95% radiochemical purity were found after 72 hours at 25 °C. Even under short term elevated temperature conditions (32°C for 12 h and 25° for 60 h) such high stability was found with respect to radiochemical purity.
  • the use of two stabilizers has been found to be of particular suitability in stabilizing sensitive radiopharmaceutical solutions.
  • the presence of one stabilizer during complex formation and another stabilizer added after the complex formation is of advantage as it ensures that already during the complexation reaction, the cell receptor-binding molecule is protected against radiolysis and the other stabilizer enhances the protecting effect for the shelf-life period.
  • a shelf-life of at least 3 days is required to allow a radiopharmaceutical drug product to be manufactured from a centralized pharmaceutical production site and to commercialize it as a ready-to-use drug product.
  • the present invention allows centralized pharmaceutical production at highest quality standards (e.g. cGMP) and at industrial scale, e.g. at 74 GBq or 148 GBq batch size which provides the drug product in numerous dose units, e.g. enough dose units for the treatment of 10 to 20 patients at the same time.
  • highest quality standards e.g. cGMP
  • industrial scale e.g. at 74 GBq or 148 GBq batch size which provides the drug product in numerous dose units, e.g. enough dose units for the treatment of 10 to 20 patients at the same time.
  • the present invention of particular suitability for the somatotatin receptor binding peptides, here in particular for the very sensitive somatostatin analogues octreotide and octreotate which are in particular prone to degradation reactions. Further, the present invention of particular suitability for the radionuclide Lutetium-177 with its specific radioactivity characteristics.
  • a pharmaceutical aqueous solution comprising
  • said radionuclide is present in a concentration that it provides a volumetric radioactivity of at least 100 MBq/mL, preferably of at least 250 MBq/mL.
  • said stabilizer(s), component (b), is (are) present in a total concentration of at least 0.2 mg/ml_, preferably at least 0.5 mg/ml_, more preferably at least 1 .0 mg/ml_, even more preferably at least 2.7 mg/mL.
  • radionuclide is present in a concentration that it provides a volumetric radioactivity of from 100 to 1000 MBq/mL, preferably from 250 to 500 MBq/mL.
  • component (b) is only one stabilizers against radiolytic degradation, i.e. only a first stabilizer.
  • component (b) are at least two stabilizers against radiolytic degradation, i.e. at least a first and a second stabilizer, prefably only two stabilizers, i.e. only a first and a second stabilizer.
  • the pharmaceutical aqueous solution according to any one of the preceding embodiments wherein the stabilizer(s) is (are) selected from gentisic acid (2,5- dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g. sodium ascoorbate), methionine, histidine, melatonine, ethanol, and Se-methionine, preferably selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.
  • the first stabilizer is selected from gentisic acid and ascorbic acid, preferably the first stabilizer is gentisic acid.
  • radionuclide is selected from 177 Lu, 68 Ga, 18 F, 99m Tc, 211 At, 82 Rb, 166 Ho, 225 Ac, 111 In, 123 l, 131 l, 89 Zr, 90 Y, preferably selected from 177 Lu and 68 Ga, more preferably is 177 Lu.
  • the cell receptor binding moiety is a somatostatin receptor binding peptide
  • said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.
  • chelating agent is selected from DOTA, DTPA, NTA, EDTA, D03A, NOC and NOTA, preferably is DOTA.
  • a buffer preferably said buffer is an acetate buffer, preferably in an amount to result in a concentration of from 0.3 to 0.7 mg/ml_ (preferably about 0.48 mg/ml_) acetic acid and from 0.4 to 0.9 mg/ml_ (preferably about 0.66 mg/ml_) sodium acetate.
  • a sequestering agent preferably said sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount to result in a concentration of from 0.01 to 0.10 mg/ml_ (preferably about 0.05 mg/ml_).
  • DTPA diethylentriaminepentaacetic acid
  • the pharmaceutical aqueous solution according to any one of the preceding embodiments which has a shelf life of at least 24 hours (h) at ⁇ 25 °C, at least 48 h at ⁇ 25 °C, at least 72 h at ⁇ 25 °C, of from 24 h to 120 h at ⁇ 25 °C, from 24 h to 96 h at ⁇ 25 °C, from 24 h to 84 h at ⁇ 25 °C, from 24 h to 72 h at ⁇ 25 °C, in particular has a shelf life of 72 h at ⁇ 25 °C. 21 .
  • a pharmaceutical aqueous solution comprising
  • the pharmaceutical aqueous solution according to any one of the preceding embodiments further comprising a sequestering agent, added after the complex formation of components (ai) and (aii), for removing any uncomplexed Lu, preferably said sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount to result in a concentration of from 0.01 to 0.10 mg/ml_ (preferably about 0.05 mg/ml_) in the final solution.
  • DTPA diethylentriaminepentaacetic acid
  • step (2.2.) mixing the complex solution obtained by step (1 ) with the dilution solution obtained by the step (2.1).
  • step (1 .2) further comprises a buffer, preferably an acetate buffer.
  • step (1 .3) the resulting mixture is heated to a temperature of from 70 to 99 °C, preferably from 90 to 98 °C, for from 2 to 59 min.
  • step (2.1) further comprises diethylentriaminepentaacetic acid (DTPA) or a salt thereof.
  • DTPA diethylentriaminepentaacetic acid
  • step (3) Dispensing the filtered solution obtained by step (3) into dose unit containers in a volume required to deliver the radioactive dose of from 5.0 to 10 MBq, preferably from 7.0 to 8.0 MBq, more preferably from 7.3 to 7.7 MBq, even more preferably from 7.4-7.5 MBq, preferably said volume is from 10 to 50 ml_, more preferably from 15 to 30 ml_, even more preferably from 20 to 25 ml_.
  • step (1 .1) comprises l_uCI 3 and HCI.
  • step (1 .2) comprises 177 Lu-DOTA-TATE or 177 Lu- DOTA-TOC, gentisic acid, acetic acid, and sodium acetate.
  • step (2.1 ) comprises DTPA, and ascorbic acid.
  • step (4) The process according to any one of embodiments 32 to 43, wherein the dose unit containers in step (4) are stoppered vials, enclosed within a lead container.
  • aqueous solution a solution of a solute in water.
  • the radionuclide metal ion is forming a non-covalent bond with the functional groups of the chelating agent, e.g. amines or carboxylic acids.
  • the chelating agent has at least two such complexing functional groups to be able to form a chelate complex.
  • the chelating agent in the context of the present invention may be
  • DOTA 1 ,4,7,10-Tetraazacyclododecane-1 ,4,7,10-tetraacetic acid
  • NTA Nitrilotriacetic acid
  • D03A 1 ,4,7,10-Tetraazacyclododecane-1 ,4,7-triacetic acid
  • DOTA DOTA
  • “cell receptor binding moiety” for which the present invention is in particular suitable is a somatostatin receptor binding peptide, preferably said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.
  • linking bond(s) is (are) either covalent or non-covalent bond(s) between the cell receptor binding organic moiety (and the linker) and the chelating agent, preferably the bond(s) is (are) covalent.
  • “Stabilizer against radiolytic degradation” stabilizing agent which protects organic molecules against radiolytic degradation, e.g. when a gamma ray emitted from the radionuclide is cleaving a bond between the atoms of an organic molecules and radicals are forms, those radicals are then scavenged by the stabilzer which avoids the radicals undergo any other chemical reactions which might lead to undesired, potentially ineffective or even toxic molecules. Therefore, those stabilizers are also referred to as“free radical scavengers” or in short “radical scavengers”. Other alternative terms for those stabilizers are “radiation stability enhancers”, “radiolytic stabilizers”, or simply “quenchers”.
  • stabilizer(s) is (are) present in the solution during the complex formation of components (ai) and (aii)”: first stabilizer present and optionally also second stabilizer present, i.e. either first stabilizer alone or in combination with second stabilizer present
  • stabilizer(s) are in either the radionuclide solution or in the chelating agent containing solution before those two solutions are added and potentially elevated temperatures are applied to facilitate the complex formation.
  • the stabilizer(s) are in the chelating agent containing solution.
  • the second stabilizer is added after the complex forming reaction is completed, e.g. after the reacting solution which might have been heated up to an elevated temperature is again cooled down to ambient temperature.
  • the cell receptor binding moiety and the chelating agent may form together the following molecules:
  • DOTA-OC [DOTA°,D-Phe 1 ]octreotide
  • DOTA-TOC [DOTA°,D-Phe 1 ,Tyr 3 ]octreotide, edotreotide,
  • DOTA-NOC [DOTA°, D-Phe 1 ,l-Nal 3 ]octreotide
  • DOTA-TATE [DOTA°,D-Phe 1 ,Tyr 3 ]octreotate, oxodotreotide
  • DOTA-LAN [DOTA°,D-p-Nal 1 ]lanreotide
  • DOTA-VAP [DOTA°,D-Phe 1 ,Tyr 3 ]vapreotide.
  • the preferred molecules for the present invention are DOTA-TOC and DOTA-TATE, more preferably the molecule is DOTA-TATE.
  • Buffer for a pH from 4.5 to 6.0 may be an acetate buffer, citrate buffer (e.g. citrate + HCI or citric acid + Disodium hydrogenphosphate) or phosphate buffer (e.g. Sodium dihydrogenphosphate + Disodium hydrogenphosphate), preferably said buffer is an acetate buffer, preferably said acetate buffer is composed of acetic acid and sodium acetate.
  • Radionuclide metal ions preferably DTPA: Diethylentriaminepentaacetic acid.
  • the drug product is able to obtain marketing authorization by health authorities, is able to be manufactured from at a pharmaceutical production site at commercial scale and is able to be supplied to remotely located end users, e.g. hospitals or patients.
  • the 177 LUCI 3 may be obtained from commercial sources, e.g. I.D.B. Holland BV.
  • the DOTA°- Tyr ⁇ -Octreotate may be obtained from commercial sources, e.g. by piCHEM Anlagens- undtechniks GmbH, Austria. All other components of the drug product are commercially available from various sources.
  • Example 1 Composition of drug product
  • the Drug Product ( 177 Lu-DOTA°-Tyr 3 -Octreotate 370 MBq/mL solution for infusion) is designed as a sterile ready-to-use solution for infusion containing 177 Lu-DOTA°-Tyr 3 - Octreotate as Drug Substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time (tc)).
  • the shelf-life of Drug Product is defined as 72 hours after calibration time.
  • Drug Product is a single dose vial, containing suitable amount of solution that allows delivery of 7.4 GBq of radioactivity at injection time.
  • Manufacturing site prepares single doses calibrated within the range of 7.4 GBq ⁇ 10 %
  • RSE Radiation Stability Enhancer Example 2: Manufacturing of drug product
  • a 177 LuCI 3 solution 74 GBq in HCI, is mixed together with a DOTA-Tyr ⁇ -Octreotate solution, 2 mg and a Reaction Buffer solution, containing an antioxidant agent (i.e. Gentisic acid) and a buffer system (i.e. Acetate buffer system) able to allow the radiolabelling that occurs at temperature 90 to 98°C for several minutes.
  • an antioxidant agent i.e. Gentisic acid
  • a buffer system i.e. Acetate buffer system
  • the synthesis is carried out using a single use disposable kit cassette installed on the front of the synthesis module which contains the fluid pathway (tubing), reactor vial and sealed reagent vials.
  • the obtained mother solution is diluted with a solution containing a chelating agent (i.e. DTPA) and an antioxidant agent (i.e. ascorbic or gentisic acid) and, then, sterile filtered through 0.2 pm to give the ready-to-use solution as described in Example 1 .
  • a chelating agent i.e. DTPA
  • an antioxidant agent i.e. ascorbic or gentisic acid
  • the solution is dispensed in volumes of from 20.5 to 25.0 ml_ into sterile vials.
  • the stoppered vials are enclosed within lead containers for protective shielding.
  • Example 3 Stability study results after storage at various temperature conditions.
  • the following table provides the stability test data for a batch produced at 74 GBq batch size according to the process described in Example 2.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des solutions complexes de radionucléides de concentration élevée et de stabilité chimique élevée, qui permettent leur utilisation en tant que médicament à des fins diagnostiques et/ou thérapeutiques. La stabilité du produit médicamenteux est obtenue par utilisation d'au moins un stabilisant contre la dégradation radiolytique. L'utilisation de deux stabilisateurs introduits pendant le processus de fabrication à différents stades s'est révélée être particulièrement avantageuse.
PCT/IB2018/055575 2018-07-25 2018-07-25 Solutions complexes de radionucléides, stables, concentrées WO2020021310A1 (fr)

Priority Applications (34)

Application Number Priority Date Filing Date Title
PCT/IB2018/055575 WO2020021310A1 (fr) 2018-07-25 2018-07-25 Solutions complexes de radionucléides, stables, concentrées
JP2021504214A JP7358451B2 (ja) 2018-07-25 2018-07-25 安定な濃厚放射性核種錯体溶液
PCT/IB2018/057415 WO2020021322A1 (fr) 2018-07-25 2018-09-25 Solutions complexes concentrées stables de radionucléides
AU2018433575A AU2018433575B2 (en) 2018-07-25 2018-09-25 Stable, concentrated radionuclide complex solutions
BR112021001148-0A BR112021001148A2 (pt) 2018-07-25 2018-09-25 soluções estáveis de complexo de radionuclídeo concentrado
KR1020247006883A KR20240033296A (ko) 2018-07-25 2018-09-25 안정한 농축 방사성 핵종 복합체 용액
CA3153630A CA3153630A1 (fr) 2018-07-25 2018-09-25 Solutions complexes concentrees stables de radionucleides
CN201880095724.5A CN112584875A (zh) 2018-07-25 2018-09-25 稳定的、浓缩的放射性核素络合物溶液
EP18783136.7A EP3826686A1 (fr) 2018-07-25 2018-09-25 Solutions complexes concentrées stables de radionucléides
US16/140,962 US20200030466A1 (en) 2018-07-25 2018-09-25 Stable, concentrated radionuclide complex solutions
MX2021000805A MX2021000805A (es) 2018-07-25 2018-09-25 Soluciones de complejos de radionuclidos estables y concentradas.
SG11202100645XA SG11202100645XA (en) 2018-07-25 2018-09-25 Stable, concentrated radionuclide complex solutions
DE202018006567.6U DE202018006567U1 (de) 2018-07-25 2018-09-25 Stabile, konzentrierte Radionuklidkomplexlösungen
JP2021504167A JP7402218B2 (ja) 2018-07-25 2018-09-25 安定な濃厚放射性核種錯体溶液
KR1020217005212A KR102643582B1 (ko) 2018-07-25 2018-09-25 안정한 농축 방사성 핵종 복합체 용액
US16/175,261 US10596276B2 (en) 2018-07-25 2018-10-30 Stable, concentrated radionuclide complex solutions
US16/175,239 US10596278B2 (en) 2018-07-25 2018-10-30 Stable, concentrated radionuclide complex solutions
TW108124451A TW202019489A (zh) 2018-07-25 2019-07-11 穩定的、濃縮的放射性核種錯合物溶液
ARP190102070A AR119655A1 (es) 2018-07-25 2019-07-23 Soluciones de complejos de radionúclidos estables y concentradas
EP19773177.1A EP3826687A1 (fr) 2018-07-25 2019-07-24 Procédé de traitement de tumeurs neuroendocrines
US17/263,140 US20220072166A1 (en) 2018-07-25 2019-07-24 Method of treatment of neuroendocrine tumors
JP2021504165A JP2021531306A (ja) 2018-07-25 2019-07-24 神経内分泌腫瘍の処置の方法
CN201980048954.0A CN112955188A (zh) 2018-07-25 2019-07-24 治疗神经内分泌肿瘤的方法
PCT/IB2019/056315 WO2020021465A1 (fr) 2018-07-25 2019-07-24 Procédé de traitement de tumeurs neuroendocrines
US16/827,606 US11904027B2 (en) 2018-07-25 2020-03-23 Stable, concentrated radionuclide complex solutions
CONC2021/0000506A CO2021000506A2 (es) 2018-07-25 2021-01-20 Soluciones de complejos de radionúclidos estables y concentradas
IL280314A IL280314A (en) 2018-07-25 2021-01-20 Complex solutions of radionuclide are stable and concentrated
US17/209,122 US20210379213A1 (en) 2018-07-25 2021-03-22 Stable, concentrated radionuclide complex solutions
AU2022203683A AU2022203683B2 (en) 2018-07-25 2022-05-30 Stable, concentrated radionuclide complex solutions
JP2023085193A JP2023117417A (ja) 2018-07-25 2023-05-24 安定な濃厚放射性核種錯体溶液
JP2023085502A JP2023126209A (ja) 2018-07-25 2023-05-24 安定な濃厚放射性核種錯体溶液
US18/494,042 US20240075171A1 (en) 2018-07-25 2023-10-25 Stable, concentrated radionuclide complex solutions
JP2023219738A JP2024038132A (ja) 2018-07-25 2023-12-26 神経内分泌腫瘍の処置の方法
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