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
  • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
• • 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
  • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
• • 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
  • 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
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/121—Solutions, i.e. homogeneous liquid formulation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
  • C07B59/008—Peptides; Proteins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/13—Labelling of peptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/575—Hormones
  • C07K14/655—Somatostatins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2123/00—Preparations for testing in vivo
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• the present disclosure relates to methods of large scale synthesis of radionuclide complex solutions having a high activity for diagnostic and/or therapeutic purposes, their use in the commercial production of radioactive drug substances, and to respective solutions as well as containers comprising said solutions.
• Background Art The concept of targeted drug delivery is based on cell receptors or other cell surface markers 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 surface markers, it allows the delivery of the drug after its systemic administration in high concentration to those target cells while leaving other cells, which are not of interest, unaffected.
• a target binding moiety is typically linked to a chelating moiety which is able to form a strong complex with the metal ions of a radionuclide.
• This radionuclide complex is then delivered to the target cell and the decay of the radionuclide is then releasing high energy electrons, positrons or alpha particles as well as gamma rays at the target site.
• the radionuclide complex is preferably produced in a shielded closed-system due to significant radioactivity.
• purification and formulation steps of the drug substance are part of a continuous process.
• the decay of the radionuclide does not allow enough time for any interruption of the production process of the drug substance. Otherwise the desired activity of a drug product would not be attained putting diagnostic or therapeutic outcome at risk. Therefore, preferably no tests may be performed at critical steps and no synthesis intermediates may be isolated and controlled in the course of production.
• a synthesis method for the production of radionuclide complexes as radioactive drug substance shall have the following advantages: - a high labelling yield correlating with high radiochemical purity, - a high labelling yield with minimized level of free (uncomplexed) radionuclide, - a production of a larger number of doses per batch in comparison to conventional methods.
• the present disclosure relates to a reaction solution for radiolabeling a target binding organic molecule with 177 Lu(III) ions, wherein said reaction solution comprises: (1) 177 Lu(III) ions in a volumetric activity of at least 17 GBq/mL, (2) a target binding organic molecule comprising a target binding organic moiety linked to a chelating moiety suitable for chelating Lu(III) ions, and (3) one or more stabilizers against radiolytic degradation.
• the present disclosure also relates to a mother solution for preparing a dispensing solution comprising 177 Lu radiolabeled target binding organic molecule, wherein said mother solution comprises: (1) 177 Lu(III) ions in a volumetric activity of at least 10 GBq/mL, (2) a radionuclide complex formed by a target binding organic molecule comprising a target binding organic moiety linked to a chelating moiety and the 177 Lu(III) ions, (3) one or more stabilizers against radiolytic degradation, and (4) an oxygen concentration lower than 50 mg/L, preferably lower than 20 mg/L, more preferably lower than 10 mg/L, even more preferably lowever than 5 mg/L, even more preferably lower than 3 mg/L at 25 deg C.
• the present disclosure also relates to a mother solution container for collecting solutions from a radiolabeling reaction, wherein said container comprises: (1) a mother solution comprising: a. 177 Lu(III) ions in a volumetric activity of at least 10 GBq/mL, b. a radionuclide complex formed by a target binding organic molecule comprising a target binding organic moiety linked to a chelating moiety and the 177 Lu(III) ions, c. one or more stabilizers against radiolytic degradation, and (2) a headspace gas volume above the mother solution, wherein said headspace gas volume contains not more than 10 vol% oxygen.
• the present disclosure also relates to a process for manufacturing a radiopharmaceutical solution comprising the steps: (1) providing a reaction solution, (2) reacting a target binding organic molecule comprising a target binding organic moiety linked to a chelating moiety with 177 Lu(III) ions at below atmospheric pressure, optionally in the presence of an inert gas, to obtain a radionuclide complex in a single container for radiolabeling.
• the present disclosure also relates to a product which is obtainable or obtained by the method as described herein.
• the present disclosure also relates to aqueous solutions comprising radionuclide complexes.
• reaction solution refers to a solution comprising ions of a radionuclide, a target binding organic molecule which is suitable for chelating the radionuclide ions, and one or more stabilizers against radiolytic degradation.
• the target binding organic molecule comprises a target binding organic moiety linked directly or indirectly to a chelating moiety.
• the term “mother solution” refers to a solution which is obtained when the aforesaid reaction solution has finished reacting forming radionuclide complexes, has been processed as described further below (if applicable) and has been mixed and diluted with water for injection (WFI) (if applicable).
• the term “dispensing solution” refers to a solution which is obtained when the aforesaid mother solution has been additionally mixed with a dilution solution.
• the dispensing solution comprises all the components and an activity that is suitable for patient administration.
• the dispensing solution is the solution that is dispensed into multiple patient doses (vials), which are destined for subsequent administration to a patient without further material change.
• radionuclide includes, without limitation, the radioactive isotopes of I, In, Tc, Ga, Cu, Zr, Pb, Bi, Ac, Th, Re, Sc, Tb, Y and Lu, and in particular: 131 I, 111 In, 99m Tc, 68 Ga, 64 Cu, 67 Cu, 89 Zr, 212 Pb, 213 Bi, 225 Ac, 227 Th, 47 Sc, 188 Re, 161 Tb, 90 Y, 177 Lu.
• the ions of the radioisotopes form non-covalent bonds with the functional groups of the chelating agent, e.g. amino groups or carboxyl groups.
• the radionuclide ions comprise lutetium-177 ( 177 Lu) ions.
• the radionuclide ions may originate from 177 LuCl 3 in HCl solution.
• the term “stabilizer against radiolytic degradation” refers to a stabilizing agent which protects organic molecules against radiolytic degradation, e.g.
• 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) present in the solutions of the present disclosure may be selected from gentisic acid (2,5-dihydroxybenzoic acid) or salts thereof, ascorbic acid (L-ascorbic acid, vitamin C) or salts thereof (e.g. sodium ascorbate), methionine, histidine, melatonine, ethanol, and Se- methionine, preferably selected from gentisic acid or salts thereof, preferably not ethanol.
• the reaction solution and mother solution do not include ascorbic acid, preferably they include gentisic acid as stabilizer agent but not ascorbic acid.
• the reaction solution and mother solution do not include ethanol as stabilizing agent.
• the reaction solution and mother solution do not include either of ascorbic acid and ethanol as stabilizers.
• the “about” indicates a deviation of the value or range by ⁇ 20%, preferably ⁇ 10%, more preferably ⁇ 5%, potentially ⁇ 2% or ⁇ 1%.
• Lutetium-177 is accessible via (n, ⁇ ) reaction.
• One method comprises irradiation of 176 Lu, leading to the direct formation of 177 Lu.
• this method leads to concomitant formation of the metastable 177m Lu isotope and other lutetium isotopes.
• compositions comprising 177 Lu and 177m Lu and others may be used.
• Such a composition comprising 177 Lu and related isotopes is called carrier-added 177 Lu source or 177 Lu (C.A.) source.
• the second method involves beta decay of the short-lived radioisotope 177 Yb (half-life of 1.9 hours), which is produced by neutron capture of enriched 176 Yb (> 99%) target.
• the low thermal neutron cross section of the 176 Yb (n, ⁇ ) 177 Yb reaction results in a production of only very small amounts of the desired 177 Lu in comparison with the total mass of the target.
• the target binding molecule for use according to the disclosure comprises (i) a targeting binding organic moiety, linked to (ii) a chelating moiety, either directly or indirectly via a linker.
• a targeting binding organic moiety refers to an organic moiety which has specific binding affinity to a target protein, typically a cell surface receptor or cellular protein.
• said target binding receptor moiety is an organic moiety which has specific binding affinity to somatostatin receptor, for example at least somatostatin receptor subtype 2 (SSTR2) or an organic moiety which has binding affinity to prostate specific membrane antigen (PSMA).
• Other targets/target binding organic moieties may be Gastrin-Releasing Peptide Receptor (GRPR) antagonists, ligands targeting ⁇ v ⁇ 3/ ⁇ v ⁇ 5 integrins, fibroblast activation protein (FAP) inhibitors.
• GRPR Gastrin-Releasing Peptide Receptor
• FAP fibroblast activation protein
• chelating moiety refers to an organic moiety comprising functional groups that form non-covalent bonds with a radionuclide during the reacting step of the method and, thereby, form a stable radionuclide complex.
• the chelating moiety in the context of the present invention may be or may comprise 1,4,7,10-Tetraazacyclododecane- 1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-Tetraazacyclododecane-1-(glutaric acid)- 4,7,10 -triacetic acid (DOTAGA), diethylentriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid (DO3A), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1-(1,3- carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane (NODAGA) or mixtures or variants thereof, preferably DOTA.
• DOTA 1,4,7,10-T
• Such chelating moiety is either directly linked to the target binding organic moiety or connected via a linker molecule, preferably it is directly linked.
• the linking bond(s) is (are) either covalent or non-covalent bond(s) between the target binding organic moiety (and the linker) and the chelating moiety, preferably the bond(s) is (are) covalent.
• said target binding organic molecule comprises somatostatin receptor binding peptides.
• somatostatin receptor binding peptide refers to a peptidic moiety with specific binding affinity to the somatostatin receptor for example at least somatostatin receptor subtype 2 (SSTR2).
• said target-binding molecule for use as described herein is a compound of formula C-S-P wherein : ⁇ C is a chelating agent capable of chelating a radionuclide; ⁇ S is an optional spacer covalently linked between C and P; ⁇ P is a somatostatin receptor binding peptide covalently linked to C, for example via its N-terminal end, either directly or indirectly via S.
• somatostatin receptor binding peptide may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.
• somatostatin receptor binding peptide refers to a peptidic moiety with specific binding affinity to somatostatin receptor.
• Such somatostatin receptor binding peptide may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.
• the somatostatin receptor-binding peptide linked to a chelating moiety may comprise a chelating moiety selected from the group comprising DOTA, DOTAGA, DTPA, NTA, EDTA, DO3A, NOTA, NODAGA.
• the somatostatin receptor-binding peptide linked to a chelating moiety comprises preferably DOTA.
• the target binding organic moiety linked to the chelating moiety wherein the target binding organic moiety is a somatostatin receptor- binding peptide may be selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.
• the cell receptor binding moiety and the chelating agent may form together the following molecules: DOTA-OC: [DOTA 0 ,D-Phe 1 ]octreotide, DOTA-TOC: [DOTA 0 ,D-Phe 1 ,Tyr 3 ]octreotide, edotreotide (INN), represented by the following formulas:
• DOTA-NOC [DOTA 0 , D-Phe 1 ,1-Nal 3 ]octreotide
• DOTA-TATE [DOTA 0 ,D-Phe 1 ,Tyr 3 ]octreotate
• DOTA-Tyr 3 -Octreotate DOTA-d-Phe- Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo 2,7)
• oxodotreotide (INN) represented by the following formula :
• DOTA-LAN [DOTA 0 ,D- ⁇ -Nal 1 ]lanreotide
• DOTA-VAP [DOTA 0 ,D-Phe 1 ,Tyr 3 ]vapreotide.
• Satoreotide trizoxetan
• said target binding organic molecule comprises a PSMA-binding moiety.
• the PSMA-binding moiety may comprise one or more glutamate-urea-lysine moieties.
• the PSMA-binding organic molecule may comprise a chelating moiety selected from the group comprising DOTA, DOTAGA, DTPA, NTA, EDTA, DO3A, NOTA, NODAGA, preferably DOTA or DOTAGA, more preferably DOTA.
• the target binding organic molecule is a PSMA- binding peptide preferably selected from PSMA-617, wherein PSMA-617 has the structure , or variants of PSMA-617 with additional structural features like albumin-binding moieties; PSMA-I&T, wherein PSMA-I&T has the structure
• PSMA-R2 wherein PSMA-R2 has the structure HOOC HOOC N N O Br N N HOOC N N H O O COOH HOOC N N COOH H H with the Glu and Lys residue being in the L-configuration, with PSMA-617 being preferred.
• PSMA ligand or PSMA-binding organic molecule many be selected from the group consisting of PSMA-617, PSMA I&T, PSMA-R2, MIP- 1095, MIP-1545, MIP, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY- 2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, PSMA-7 I&T, EB- PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, and RPS-074, preferably selected from the group consisting of PSMA-617, PSMA I&T, and PSMA-R2, more preferably PSMA-617.
• the reaction solution concerns a reaction solution which comprises reactants which are necessary to form a radionuclide complex by way of a reaction.
• Such reactants are a radionuclide and a target binding organic molecule.
• the reaction of forming a radionuclide complex from said two reactants is also called radiolabelling.
• the reaction solution is used for and is suitable for radiolabelling a target binding organic molecule with a radionuclide.
• the target binding organic molecule comprises (i) a targeting binding organic moiety, linked to (ii) a chelating moiety, either directly or indirectly via a linker, as described above in the preceding section.
• the reaction solution additionally comprises one or more stabilizers against radiolytic degradation.
• the radionuclide may preferably be lutetium-177 ( 177 Lu) in the form of 177 Lu(III) ions.
• the radionuclide ions may originate from 177 LuCl 3 in HCl solution.
• the reaction solution may comprise the 177 Lu(III) ions in a volumetric activity of at least 17 GBq/ml, or 18 GB/q/ ml, preferably at least 19 GBq/ml and more preferably at least 20 GBq/mL, even more preferably at least 25 GBq/mL, even more preferably at least 28 GBq/mL, even more preferably at least 30 GBq/mL.
• Upper limits in relating to the before mentioned minimum values may be 20, 25, 30, 40, 50 GBq/mL.
• the present disclosure is related to a reaction solution for radiolabeling a target binding organic molecule with 177 Lu(III) ions, wherein said reaction solution comprises: (1) 177 Lu(III) ions in a volumetric activity of at least 17 GBq/mL, (2) a target binding organic molecule comprising a target binding organic moiety linked to a chelating moiety suitable for chelating Lu(III) ions, and (3) one or more stabilizers against radiolytic degradation.
• the reaction solution may comprise an oxygen concentration lower than 50 mg/L, preferably lower than 20 mg/L, more preferably lower than 10 mg/L, even more preferably lowever than 5 mg/L, even more preferably lower than 3 mg/L at 25 deg C or an oxygen concentration which is lower than 7 mg/L or 6 mg/L, or 5 mg/L, preferably lower than 4 mg/L, more preferably lower than 3 mg/L, more preferably lower than 2 mg/L or 1 mg/L (all values at 25 degrees Celsius).
• Oxygen may be substantially absent in the reaction solution.
• a low oxygen concentration in the reaction solution reduces radiolytic degradation. The low levels/absence of oxygen may be achieved by degassing and/or flushing the reaction solution with a protection gas, such as nitrogen or argon.
• Lu(III) ions may be comprised in the reaction solution in a volumetric activity of at least 17 GBq/ml, or 18 GBq/ml, preferably 19 GBq/ml and more preferably 20 GBq/ml, even more preferably at least 28 GBq/mL, even more preferably at least 30 GBq/mL.
• Upper limits in relating to the before mentioned minimum values may be 20, 25, 30, 40, 50 GBq/mL.
• the reaction solution contains one or more stabilizers against radiolytic degradation and these may comprise gentisic acid or a salt thereof.
• the concentration of gentisic acid or a salt thereof may be from 5 to 15 mg/mL.
• the concentration of gentisic acid or salt thereof may be 10 to 15 mg/mL. In case the target binding organic moiety linked to a chelating moiety is a PSMA-binding peptide, the concentration of gentisic acid or salt thereof is from 5 to 10 mg/mL.
• the reaction solution may comprise ascorbic acid or a salt thereof in not more than 5% (w/w), preferably not more than 2%, even more preferably not more than 1%. Most preferably, the reaction solution does not comprise ascorbic acid, i.e. it is substantially absent (substantially 0%).
• the reaction solution may comprise ethanol in not more than 5%(w/w), preferably not more than 2%, even more preferably not more than 1%. Most preferably, the reaction solution does not comprise ethanol, i.e. it is substantially absent (substantially 0%). In preferred embodiments, ascorbic acid or salts thereof and ethanol are substantially not included in the reaction solution.
• the reaction solution may comprise the target binding organic molecule in molar excess to the 177 Lu(III) ions, even when the 177 Lu(III) ions originate from a non-carrier-added (N.C.A.) 177 Lu(III) ion source.
• the molar ratio between the target binding organic molecule and the 177 Lu(III) ions may be at least 1.2, preferably between 1.5 and 3.5.
• the reaction solution may comprise the target binding organic molecule in molar excess to the group of all Lu(III) ions including 177 Lu(III) ions, 176 Lu(III) ions, 175 Lu(III), and metastable 177m Lu(III) ions, which are present in the composition that provides the 177 Lu(III) ions at the volumetric activity given above for use in the instant reaction solution, when carrier-added (C.A.) 177 Lu(III) is used as a source of 177 Lu(III) ions.
• the molar ratio between the target binding organic molecule and the group of all Lu(III) ions including 177 Lu(III) ions, 176 Lu(III) ions, 175 Lu(III), and metastable 177m Lu(III) ions may be at least 1.2, preferably between 1.5 and 3.5.
• the reaction solution may comprise a pharmaceutically acceptable buffer to provide a pH in the range of 2 to 8, which is suitable for the reaction between the 177 Lu(III) ions and the target binding organic molecule.
• the pharmaceutically acceptable buffer preferably provides a pH in the range of 4 to 6.
• the pharmaceutically acceptable buffer comprises acetate buffer, citrate buffer or a phosphate buffer.
• the citrate buffer may comprise a citrate and HCl and/or citric acid.
• the phosphate buffer may comprise sodium dihydrogen phosphate and disodium hydrogen phosphate.
• the pharmaceutically acceptable buffer comprises preferably an acetate buffer, which is preferably composed of acetic acid and sodium acetate.
• the mother solution The present disclosure concerns a mother solution which is a solution obtained when the reaction solution described in the preceding section has finished reacting forming radionuclide complexes, has been processed as described further below and has been mixed and diluted with water for injection (WFI). As the radiolabelling reaction is terminated, the mother solution comprises a radiolabelled target binding organic molecule, which is a radionuclide complex formed by the target binding organic moiety linked directly or indirectly to a chelating moiety and the 177Lu(III) ions described above.
• the mother solution is used for and is suitable for subsequently preparing a dispensing solution.
• the dispensing solution is a solution that is dispensed into multiple patient doses (vials), which are destined for subsequent administration to a patient without further material change.
• the present disclosure concerns a mother solution for preparing a dispensing solution comprising 177Lu radiolabeled target binding organic molecule, wherein said mother solution comprises: (1) 177 Lu(III) ions in a volumetric activity of at least 10 GBq/mL, (2) a radionuclide complex formed by a target binding organic molecule comprising target binding organic moiety linked to a chelating moiety and the 177Lu(III) ions, (3) one or more stabilizers against radiolytic degradation, and (4) preferably, an oxygen concentration lower than 50 mg/L, preferably lower than 20 mg/L, more preferably lower than 10 mg/L, even more preferably lower than 5 mg/L, even more preferably lower than 3 mg/L at 25 deg C or an oxygen
• the mother solution may comprise the 177 Lu(III) ions in a volumetric activity of at least 10 GBq/ml, at least 11 GBq/ml, at least 12 GBq/ml, preferably at least 13 GBq/ml, more preferably at least 15 GBq/ml most preferably at least 16 GBq/ml.
• the radionuclide complex formed by a target binding organic molecule and the 177Lu(III) ions comprises the target binding organic molecule as described above under the section “target binding molecule for use according to the disclosure”.
• the one or more stabilizers against radiolytic degradation and their specifics are those as described above with respect to the reaction solution.
• a stabilizer may be gentisic acid or its salts and in concentration ranges as described above with respect to the reaction solution.
• the oxygen concentration and its specifics are those as described above with respect to the reaction solution.
• the mother solution may additionally comprise a nitrogen concentration of up to 20 ml/L at 25 degrees Celsius or an argon concentration of up to 60ml/L at 25 degrees Celsius.
• the mother solution may comprise a nitrogen concentration in a range of 3 to 20 ml/L 25 degrees Celsius, preferably 5 to 15, more preferably 10 to 15 ml/L at 25 degrees Celsius.
• the mother solution may additionally comprise a nitrogen concentration of up to 20 mg/L at 25 degrees Celsius or an argon concentration of up to 60 mg/L at 25 degrees Celsius.
• the mother solution may comprise a nitrogen concentration in a range of 3 to 20 mg/L 25 degrees Celsius, preferably 5 to 15, more preferably 10 to 15 mg/L at 25 degrees Celsius.
• the mother solution may comprise an argon concentration of 3 to 60 mg/L at 25 degrees Celsius, preferably 10 to 50, more preferably 20 to 40 mg/L at 25 degrees Celsius.
• the presence of an inert gas like nitrogen or argon in the mother solution is a consequence of the steps leading up to the formation of the mother solution as part of the process described further below.
• the concentration of inert gas in the mother solution reduces radiolytic degradation of the components of the mother solution.
• the mother solution may comprise as preferred radionuclide complexes 177 Lu-DOTA-TOC (Lutetium ( 177 Lu) edotreotide) or 177 Lu-DOTA-TATE (Lutetium ( 177 Lu) oxodotreotide) or 177 Lu-PSMA-617 ([ 177 Lu]Lu-PSMA-617, Lutetium ( 177 Lu) vipivotide tetraxetan [INN] or Lutetium Lu 177 vipivotide teraxetan [USAN]) or 177 Lu-PSMA-I&T (Lutetium ( 177 Lu) zadavotide guraxetan).
• 177 Lu-DOTA-TOC Liutetium ( 177 Lu) edotreotide
• 177 Lu-DOTA-TATE Liutetium ( 177 Lu) oxodotreotide
• 177 Lu-PSMA-617 [ 177 Lu
• the radionuclide complex 177 Lu-PSMA-617 (Lutetium ( 177 Lu) vipivotide tetraxetan) may be also referred to as [ 177 Lu]Lu-PSMA-617, Lutetium ( 177 Lu) vipivotide tetraxetan [INN] or Lutetium Lu 177 vipivotide teraxetan [USAN], PLUVICTO, or 2-[4-[2-[[4-[[[4-[[(2S)-1-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxy- propyl]carbamoylamino]pentyl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl] carbamoyl] cyclohexyl]methylamino]-2-oxoethyl]-4,7,10-tris(carboxyl
• the molecular mass is 1216.06 g/mol and the molecular formula is C 49 H 68 177 LuN 9 O 16 .
• the chemical structure for lutetium Lu 177 vipivotide tetraxetan is shown below:
• the mother solution may comprise the radionuclide complexes 177 Lu-DOTA-TOC ( 177 Lu- edotreotide) or 177 Lu-DOTA-TATE ( 177 Lu-oxodotreotide), preferably 177 Lu-DOTA-TATE ( 177 Lu-oxodotreotide), in a volumetric activity of 12 GBq/ml to 17 GBq/ml.
• the mother solution may comprise the radionuclide complex 177 Lu PSMA-617 in a volumetric activity of 10 to 30, preferably 10 to 25, more preferably 15 to 25, even more preferably 17 to 25, even more preferably 17 to 20, even more preferably 18 to 19 GBq/ml.
• the mother solution may comprise the radionuclide complex 177 Lu-PSMA I&T in a volumetric activity of 10 to 30, preferably 10 to 25, more preferably 15 to 25, even more preferably 17 to 25, even more preferably 17 to 20, even more preferably 18 to 19 GBq/ml.
• the mother solution container The present disclosure concerns a mother solution container, which is used for collecting solutions formed in a radiolabelling reaction, preferably after completion of a radiolabelling reaction.
• the mother solution container comprises the mother solution described in the preceding section.
• the mother solution container also comprises a headspace gas volume above the mother solution.
• the present disclosure relates to a mother solution container for collecting solutions formed in a radiolabeling reaction, wherein said container comprises: (1) a mother solution comprising: a.
• 177 Lu(III) ions in a volumetric activity of at least 10 GBq/mL, b. a radionuclide complex formed by a target binding organic molecule comprising a target binding organic moiety linked to a chelating moiety and the 177 Lu(III) ions, c. one or more stabilizers against radiolytic degradation, and (2) a headspace gas volume above the mother solution, wherein said headspace gas volume contains not more than 10 vol% oxygen.
• the mother solution container comprises a headspace gas volume above the mother solution, wherein said headspace gas volume contains not more than 10 vol%, preferably not more than 7 vol%, more preferably not more than 5 vol%, most preferably not more than 3 vol% oxygen.
• the headspace gas volume may substantially contain no oxygen (substantially 0 vol%).
• a low volume percentage of oxygen in the headspace gas volume reduces radiolytic degradation of the components of the mother solution.
• the mother solution container comprises the mother solution described in the preceding section, all features and embodiments described above under the mother solution apply equally to the mother solution container.
• the mother solution container additionally comprises: (3) a stabilizer against radiolytic degradation, (4) a sequestering agent, and (5) optionally an isotonic agent.
• the stabilizer against radiolytic degradation may be selected among any stabilized mentioned herein above, preferably ascorbic acid or salts thereof. Ethanol may be present in concentrations described above under the reaction solution, but is preferably substantially not contained in the dilution solution.
• sequestering agent refers to a chelating agent suitable to complex free radionuclide metal ions in the formulation (which are not complexed with the radiolabelled peptide).
• the sequestering agent is preferably di-ethylene-triamine-penta-acetic acid (DTPA, also called pentetic acid).
• the optional isotonic agent may be any selected from monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts, preferably sodium chloride.
• the mother solution container additionally comprises: (3) a stabilizer against radiolytic degradation, preferably ascorbic acid or salts thereof, (4) a sequestering agent, preferably DTPA, and (5) optionally an isotonic agent, preferably NaCl.
• the mother solution container comprises the necessary components to constitute a dispensing solution which is suitable for dispensing into multiple patient doses (vials), which are destined for subsequent administration to a patient without further material change.
• the mother solution container comprises: (A) 177 Lu-DOTATATE in an activity in the range from 296 to 444 MBq/mL, preferably 333 to 407 MBq/ml, more preferably about 351 to 389 MBq/ml, most preferably about 370 MBq/mL (10 mCi/mL); (B) acetic acid in a concentration in the range from 0.384 to 0.576 mg/ml , preferably 0.432 to 0.528 mg/ml, more preferably 0.456 to 0.504 mg/mL, most preferably about 0.48 mg/mL; (C) an acetate salt, preferably the sodium salt thereof, in a concentration in the range from 0.528 to 0.792 mg/ml, preferably 0.594 to 0.726 mg/ml , more preferably 0.627 to 0.693 mg/mL, most preferably about 0.66 mg/mL with regard to the sodium salt; (D) gentisic acid or a salt thereof in
• the mother solution container comprises: (A) 177 Lu-PSMA-617 in an activity in the range from 800 to 1200 MGq/ml, preferably 900 to 1100 MBq/ml, more preferably 950 to 1050 MBq/ml, most preferably about 1000 MBq/mL (27 mCi/mL); (B) acetic acid in a concentration in the range from 0.24 to 0.36 mg/mL, preferably 0.27 to 0.33 mg/mL, more preferably, 0.285 to 0.315 mg/mL, most preferably about 0.3 mg/mL; (C) an acetate salt, preferably the sodium salt thereof, in the concentration in the range from 0.33 to 0.49 mg/mL, preferably 0.37 to 0.45 mg/mL, more preferably 0.39 to 0.43 mg/mL, most preferably about 0.41 mg/mL with regard to the sodium salt; (D) gentisic acid or a salt thereof in a concentration in the range from 0.3 to 1.0 mg
• the process for manufacturing a radiopharmaceutical solution also relates to a process for manufacturing a radiopharmaceutical solution, which affords the solutions and the container, respectively, presenting the features described in the preceding sections.
• the process for manufacturing a radiopharmaceutical solution comprises the steps: (1) providing a reaction solution, (2) reacting a target binding organic molecule comprising a target binding organic moiety linked to a chelating moiety with 177 Lu(III) ions at below atmospheric pressure, optionally in the presence of an inert gas, to obtain a radionuclide complex in a single container for radiolabeling.
• Step (1) concerns the reaction solution as described above under the section reaction solution, so that all features and embodiments described above apply equally to the reaction solution referred to in this section.
• Step (1) of providing the reaction solution may comprise mixing the individual components described above.
• the stabilizer against radiolytic degradation may be mixed with the 177 Lu(III) ions prior to its mixing with the target binding organic moiety linked to a chelating moiety.
• Said individual components may be mixed under ambient atmosphere and ambient pressure to form the reaction solution.
• Step (1) may alternatively comprise mixing the individual components described herein at below atmospheric pressure to form the reaction solution. Below atmospheric pressure comprises a pressure range that is suitable to remove gaseous components from a container up to removing gaseous components from a solution, but a pressure that would lead to significant evaporation of the solvent (water) is to be avoided.
• the pressure may be at least 150 mbar, 200 mbar, 250 mbar or 300 mbar below atmospheric pressure up to 400 mbar, 500 mbar, 650 mbar or 700 mbar below atmospheric pressure.
• the pressure may be preferably at least around 250 mbar and up to 500 mbar below atmospheric pressure.
• Step (1) may comprise degassing solutions of the individual components described herein by letting an inert gas bubble through the solutions or purging the headspace above the individual solutions by an inert gas and then mixing the individual solutions under an inert gas atmosphere.
• Step (1) may comprise degassing solutions of the individual components described herein by letting an inert gas bubble through the solutions or purging the headspace above the individual solutions by an inert gas and then mixing the individual solutions at below atmospheric pressure to form the reaction solution.
• Below atmospheric pressure may comprise a pressure as described above. Mixing at below atmospheric pressure and/or degassing reduces the concentration of oxygen in the reaction solution, thereby reducing radiolytic degradation.
• Step (1) may comprise providing the reaction solution in a container. This is preferably one single container. Providing the reaction solution in a container may comprise applying a pressure below atmospheric pressure as described above prior to the above step of mixing the individual components in the single container.
• the reaction solution may have an activity of at least 5 Ci, preferably, of from 5 to 20 Ci, more preferably of 5-15 Ci, even more preferably of 5 - 12 , even more preferably of from about 5.4 to 12 Ci, even more preferably from 7 to 12, even more preferably from about 8 to 12 Ci.
• step (2) the target binding organic molecule and the 177 Lu(III) ions, which are comprised in the reaction solution, are reacted with each other at below atmospheric pressure to obtain a radionuclide complex composed of the target binding organic molecule and the 177 Lu(III) ions in a single container for radiolabeling.
• Below atmospheric pressure comprises applying a pressure as described above under step (1). Carrying out the reaction at below atmospheric pressure reduces radiolytic degradation.
• Step (2) comprises carrying out the reaction in one single container.
• the single container for radiolabelling comprises an oxygen concentration lower than 7 mg/L or 6 mg/L, or 5 mg/L, preferably lower than 4 mg/L, more preferably lower than 3 mg/L, more preferably lower than 2 mg/L or 1 mg/L (all values at 25 degrees Celsius).
• Oxygen may be substantially absent in the single container.
• a low oxygen concentration in the single container reduces radiolytic degradation.
• 177 Lu(III) ions may be comprised in the single container in a volumetric activity of at least 17 GBq/ml, or at least 18 GB/q/ ml, at least preferably at least 19 GBq/ml and more preferably at least 20 GBq/ml, even more preferably at least 25 GBq/mL, even more preferably at least 30 GBq/mL.
• Upper limits in relating to the before mentioned minimum values may be 20, 25, 30, 40, 50 GBq/mL.
• step (2) a molar excess of the target binding organic molecule over the 177 Lu(III) ions as described above is reacted, to ensure high radiochemical labelling yields.
• the process does not comprise any purification steps to remove free (non-chelated) 177 Lu(III) ions, such as a tC18 solid phase extraction (SPE) purification step.
• SPE solid phase extraction
• the use of a tC18 cartridge to perform a solid phase extraction (SPE) purification step to remove free (non-chelated) 177 Lu(III) ions presents some disadvantages.
• the use of this cartridge may require the elution of the product with ethanol, which is undesired (A. Mathur et al., Cancer Biother. Radiopharm.2017, 32, 266-273).
• the use of a tC18 cartridge may also remove the stabilizers, which then need to be added again (S.
• the process may comprise a step (3) of recovering the radionuclide complex, which is formed in step (2) to obtain a mother solution.
• Step (3) concerns the mother solution as described above under the section mother solution, so that all features and embodiments described above apply equally to the mother solution referred to in this section to the extent they are applicable.
• Step (3) may comprise recovering the radionuclide complex at below atmospheric pressure, wherein the pressure range is as given above.
• Step (3) may comprise recovering the radionuclide complex under an inert gas atmosphere.
• the inert gas atmosphere may be provided by nitrogen or argon.
• Step (3) of recovering the radionuclide complex may comprise introducing or transferring the mother solution into a single container affording a mother solution container.
• Step (3) concerns the mother solution container as described above under the section mother solution container, so that all features and embodiments described above apply equally to the mother solution container referred to in this section to the extent they are applicable.
• Step (3) of recovering the radionuclide complex may comprise purging the mother solution container with an inert gas before and during introducing or transferring the mother solution into the mother solution container.
• Step (3) of recovering the radionuclide complex may comprise purging the mother solution container with an inert gas at a pressure of at least 250 mbar above atmospheric pressure before and during introducing or transferring the mother solution into the mother solution container.
• the above atmospheric pressure may be at least 300 mbar, or 350 mbar or 400 mbar and up to 450 mbar or 500 mbar.
• the purging of the mother solution container with an inert gas before and during introducing or transferring of the mother solution into the mother solution container reduces radiolytic degradation of the components comprised in the mother solution container.
• the transfer from the single container of step (2) into the mother solution container of step (3) may be effected by way of the pressure above atmospheric pressure or by way of syringes.
• recovering the radionuclide complex may comprise using water-for-injection (WFI) for rinsing, i.e.
• WFI water-for-injection
• the mother solution comprises a nitrogen concentration of up to 20 ml/L at 25 degrees Celsius or an argon concentration of up to 60ml/L at 25 degrees Celsius due to the purging with nitrogen and argon, respectively.
• the mother solution may comprise a nitrogen concentration in a range of 3 to 20 ml/L 25 degrees Celsius, preferably 5 to 15, more preferably 10 to 15 ml/L at 25 degrees Celsius.
• the mother solution may comprise an argon concentration of 3 to 60 mL/L at 25 degrees Celsius, preferably 10 to 50, more preferably 20 to 40 mL/L at 25 degrees Celsius.
• the mother solution comprises a nitrogen concentration of up to 20 mg/L at 25 degrees Celsius or an argon concentration of up to 60 mg/L at 25 degrees Celsius due to the purging with nitrogen and argon, respectively.
• the mother solution may comprise a nitrogen concentration in a range of 3 to 20 mg/L 25 degrees Celsius, preferably 5 to 15, more preferably 10 to 15 mg/L at 25 degrees Celsius.
• the mother solution may comprise an argon concentration of 3 to 60 mg/L at 25 degrees Celsius, preferably 10 to 50, more preferably 20 to 40 mg/L at 25 degrees Celsius.
• step (2) reacting the target binding organic molecule with the 177 Lu(III) ions at below atmospheric pressure to obtain the radionuclide complex may be carried out over 2 to 15 minutes, preferably 4 to 10 minutes, more preferably 5 min ⁇ 0.5 min.
• step (2) reacting the target binding organic molecule with the 177 Lu(III) ions at below atmospheric pressure to obtain the radionuclide complex may be carried out at 80 to 100 degrees Celsius, preferably 90 to 98 degrees Celsius, more preferably 94 °C ⁇ 4 °C. Generally, temperatures lower than 90 degrees Celsius do not ensure quantitative labelling yields.
• a mixture volume at the step (2) of reacting the target binding organic molecule with the 177 Lu(III) ions at below atmospheric pressure to obtain the radionuclide complex may be 15 to 19 ml.
• a final volume containing the radionuclide complex after the step (3) of recovering may be between 20 to 23 ml.
• the process of the present disclosure comprising steps (1), (2) and (3) presents the technical advantage that a mother solution is obtained which comprises a radionuclide complex at a volumetric activity which has up to now not been achieved by methods of the prior art, while keeping radiolytic degradation at a minimum. The process facilitates the capturing of a higher total radioactivity originating from the radionuclide complex in the same volume of mother solution compared to published methods of e.g. the applicant.
• the process as disclosed herein affords a higher number of patient doses per given time unit than methods of the prior art. It therefore contributes to meeting the globally growing need for radiochemicals used in radiotherapy and radiodiagnosis.
• the process described herein with DOTATOC or DOTATATE as the target binding organic molecule facilitates production of radionuclide complexes having a total activity higher than 185 GBq (5 Ci) in a volume of mother solution of 20 to 23 ml.
• an embodiment of the process carried out at a total activity of 296 GBq (8 Ci) in the same volume would lead to ca. 59 to 74 patient doses of 177 Lu-DOTATOC or 177 Lu-DOTATATE (ready-for- use), considering that a single patient dose (ready for use) of 177 Lu-DOTATOC or 177 Lu- DOTATATE would typically comprise a total activity between 4 and 5 GBq (e.g. about 4.7 GBq).
• a process of the prior art that only allows for the processing of a total activity of 148 GBq (4 Ci) in the same volume would only afford ca.29 to 37 patient doses (ready-for-use).
• a therapeutic dose of 177 Lu-DOTA-TATE for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors comprises a total radioactivity of 7,400MBq at the date and time of infusion, typically within a final adjusted volume between 20.5mL and 25.0mL.
• the processes disclosed herein keep radiolytic degradation at a minimum, so that the requirements of radiochemical purity (RCP) are fulfilled. Also, the process provide for a high yield of radiolabelling.
• the process may further comprise the steps: (4) diluting the mother solution of step (3) with a dilution solution to obtain a dispensing solution at a defined volumetric activity, (5) dispensing said dispensing solution into individual patient dose units.
• Said dilution solution may comprise: (3) a stabilizer against radiolytic degradation, preferably ascorbic acid or salts thereof, (4) a sequestering agent, preferably DTPA, and (5) optionally an isotonic agent, preferably NaCl.
• the features of the stabilizer, sequestering agent and isotonic agent are as described above in the section mother solution container.
• the steps (4) and (5) afford individual patient doses which are destined for subsequent administration to a patient without further material change.
• the individual patient doses comprise a volumetric activity required for therapeutic or diagnostic purposes.
• the defined volumetric activity of the dispensing solution may be adjusted to provide individual patient dose units having a volumetric activity of 1000 MBq/mL ⁇ 5% for 177Lu-PSMA-617 and 370 MBq/mL ⁇ 5% for 177Lu-DOTA-TATE.
• the process of the present disclosure may be advantageously used for the synthesis of 177 Lu-DOTA-TATE ( 177 Lu-oxodotreotide), especially for production of a mother solution which is used for the production of 177 Lu-DOTA-TATE individual patient doses (ready-to- use).
• the dispensing solution obtained in above step (4) comprises (A) 177Lu-DOTA-TATE in an activity in the range from 296 to 444 MBq/mL, preferably 333 to 407 MBq/ml, more preferably about 351 to 389 MBq/ml, most preferably about 370 MBq/mL (10 mCi/mL); (B) acetic acid in a concentration in the range from 0.384 to 0.576 mg/ml , preferably 0.432 to 0.528 mg/ml, more preferably 0.456 to 0.504 mg/mL, most preferably about 0.48 mg/mL; (C) an acetate salt, preferably the sodium salt thereof, in a concentration in the range from 0.528 to 0.792 mg/ml, preferably 0.594 to 0.726 mg/ml , more preferably 0.627 to 0.693 mg/mL, most preferably about 0.66 mg/mL with regard to the sodium salt; (A) 177Lu-
• the dispensing solution obtained in above step (4) comprises (A) 177 Lu-PSMA-617 in an activity in the range from 800 to 1200 MBq/ml, preferably 900 to 1100 MBq/ml, more preferably 950 to 1050 MBq/ml, most preferably about 1000 MBq/mL (27 mCi/mL); (B) acetic acid in a concentration in the range from 0.24 to 0.36 mg/mL, preferably 0.27 to 0.33 mg/mL, more preferably, 0.285 to 0.315 mg/mL, most preferably about 0.3 mg/mL; (C) an acetate salt, preferably the sodium salt thereof, in the concentration in the range from 0.33 to 0.49 mg/mL,
• the process described above may be implemented in a sealed device comprising a central piece of pipe to which an inlet for inert gas, and an adaptor for applying reduced pressure to the pipe are connectable.
• containers comprising the reactants described above and water-for-injection are provided and connected to the central piece of pipe.
• containers suitable to receive the reaction solution and the mother solution are provided and connected to the central piece of pipe. All connections to the central piece of pipe are equipped with valves, so that directed transfer of solutions to and from containers is possible, effected by the application of reduced pressure or pressure of an inert gas, depending on the individual step. Transfers may alternatively be effected by the use of syringes connectable to containers and the central piece of pipe via adaptors.
• All pieces of equipment are made of materials compatible with the reagents used in the process.
• the process described above may be advantageously automated and implemented in a synthesis module employing a single use kit cassette.
• a single use kit cassette is installed on the front of a synthesis module which contains a fluid pathway (tubing), a reactor vial and sealed reagent vials.
• the disposable cassette components are made of materials specifically chosen to be compatible with the reagents used in the process.
• the components are designed to minimize potential leaching from surfaces in contact with the fluids of the process while maintaining mechanical performance and integrity of the cassette.
• the process is fully automated and takes place within a computer assisted system.
• a typical kit cassette may include (1) a reaction vial (reactor), (2) connections for incoming and outgoing fluids, (3) spikes for connecting reagent vials, and, (4) optionally, solid phase cartridges.
• the skilled person may adapt commercially available kit cassettes used for the preparation of radiopharmaceuticals such as fluorine-18 labeled radiopharmaceuticals.
• the synthesis module (and kit cassette?) comprise the following: (i) at a first position, a needle is placed for inserting in the top of a first vial containing the radioactive 177 Lu(III) solution, (ii) at a second position, a needle is placed for inserting in the top of a vial containing a solution comprising the target binding organic moiety linked to a chelating agent, (iii) at a third position, a bag with water-for-injection is installed, for rinsing steps, (iv) at a fourth position, the solution comprising one or more stabilizers against radiolytic degradation is installed, and, (v) at further positions, needles may be placed for inserting in the top of additional vials (e.g.
• mother solution container or tubing may be installed for transfer from the synthesis module to a dispensing isolator.
• Specific examples of the synthesis module and the kit cassette are described in the Examples.
• Product obtained by the process of manufacturing The present disclosure also relates to products obtained by the process of manufacturing as described above.
• a product is obtained wherein the dispensing solution comprises: (A) 177Lu-DOTA-TATE in an activity in the range from 296 to 444 MBq/mL, preferably 333 to 407 MBq/ml, more preferably about 351 to 389 MBq/ml, most preferably about 370 MBq/mL (10 mCi/mL); (B) acetic acid in a concentration in the range from 0.384 to 0.576 mg/ml , preferably 0.432 to 0.528 mg/ml, more preferably 0.456 to 0.504 mg/mL, most preferably about 0.48 mg/mL; (C) an acetate salt, preferably the sodium salt thereof, in a concentration in the range from 0.528 to 0.792 mg/ml, preferably 0.594 to 0.726 mg/ml , more preferably 0.627 to 0.693 mg/mL, most preferably about 0.66 mg/mL with regard to the sodium salt; (A) 177L
• a product is obtained wherein the dispensing solution comprises: (A) 177 Lu-PSMA-617 in an activity in the range from 800 to 1200 MBq/ml, preferably 900 to 1100 MBq/ml, more preferably 950 to 1050 MBq/ml, most preferably about 1000 MBq/mL (27 mCi/mL); (B) acetic acid in a concentration in the range from 0.24 to 0.36 mg/mL, preferably 0.27 to 0.33 mg/mL, more preferably, 0.285 to 0.315 mg/mL, most preferably about 0.3 mg/mL; (C) an acetate salt, preferably the sodium salt thereof, in the concentration in the range from 0.33 to 0.49 mg/mL, preferably 0.37 to 0.45 mg/mL, more preferably 0.39 to 0.43 mg/mL, most preferably about 0.41 mg/mL with regard to the sodium salt; (D) gentisic acid or a salt thereof in a concentration in
• Aqueous pharmaceutical solutions also relates to aqueous pharmaceutical solutions.
• the present disclosure provides the following aqueous solution: (A) 177 Lu-PSMA-617 in an activity in the range from 800 to 1200 MBq/ml, preferably 900 to 1100 MBq/ml, more preferably 950 to 1050 MBq/ml, most preferably about 1000 MBq/mL (27 mCi/mL); (B+C) a buffer to provide a pH value of the solution in the range of 4.5 to 7.0; (D) gentisic acid or a salt thereof in a concentration in the range from 0.3 to 1.0, preferably 0.3 to 0.5, more preferably 0.31 to 0.47 mg/mL, even more preferably 0.35 to 0.43 mg/mL, even more preferably 0.37 to 0.41, most preferably about 0.39 mg/mL with regard to the free acid; (E) ascorbic acid or a salt thereof, preferably the sodium salt thereof, in a concentration
• the present disclosure provides the following aqueous solution: (A) 177 Lu-PSMA-617 in an activity in the range from 800 to 1200 MBq/ml, preferably 900 to 1100 MBq/ml, more preferably 950 to 1050 MBq/ml, most preferably about 1000 MBq/mL (27 mCi/mL); (B) acetic acid in a concentration in the range from 0.24 to 0.36 mg/mL, preferably 0.27 to 0.33 mg/mL, more preferably, 0.285 to 0.315 mg/mL, most preferably about 0.3 mg/mL; (C) an acetate salt, preferably the sodium salt thereof, in the concentration in the range from 0.33 to 0.49 mg/mL, preferably 0.37 to 0.45 mg/mL, more preferably 0.39 to 0.43 mg/mL, most preferably about 0.41 mg/mL with regard to the sodium salt; (D) gentisic acid or a salt thereof in a concentration in the range from
• the aqueous solution comprises, contains, or consists of about 177 Lu-PSMA-617 (about 1,000 MBq/mL, about 27 mCi/mL), acetic acid (about 0.30 mg/mL), sodium acetate (about 0.41 mg/mL), gentisic acid (about 0.39 mg/mL), sodium ascorbate (about 50.0 mg/mL), pentetic acid (about 0.10 mg/mL), and water for injection (e.g. q.s. to 1 mL) with the pH range of the solution being from about 4.5 to about 7.0.
• the term “about” here means ⁇ 10% for all ingredients, preferably ⁇ 10% for the radioactive ingredient and ⁇ 5% for the non-radioactive ingredients.
• the present disclosure provides any one of the aqueous solutions of the embodiments above, wherein the radiochemical purity (RCP, determined by HPLC) is maintained at ⁇ 95% for at least 120 hours when stored at 30°C or below. Accordingly, the shelf-life of the aqueous solutions of the present disclosure is about 120 hours or about 5 days, preferably from the date and time of calibration, with storage conditions of below 30°C (86°F), do not freeze.
• the present disclosure provides any one of the aqueous solutions of the embodiments above, wherein said solution comprise not more than 5% (w/w) ethanol, preferably not more than 1% ethanol, more preferably does substantially not comprise any ethanol.
• the present disclosure provides any one of the aqueous solutions of the embodiments above, wherein said solution comprise a total peptide content of from 10 to 20 microgram/mL, preferably 13 to 17 microgram/mL, more preferably 14 to 16 microgram/mL, most preferably 15 microgram/mL.
• the aqueous solution of the present invention is provided as sterile, preservative-free, clear, colorless to slightly yellow solution.
• the aqueous solution is provided as ready-to-use solution.
• the present disclosure further provides individual patient dose unit with about 7.5 to about 12.5 mL content of any one of the aqueous solutions as described in any one of the embodiments above.
• Said patient dose unit may be in the form of a vial, e.g. a single-dose vial, e.g. a colorless borosilicate (type I) glass vial, e.g. of about 30 mL size, e.g. closed with a bromobutyl rubber stopper (stopper with silicate filler and inorganic coloring system) and a seal, preferably an aluminium seal, or in the form of a pre-filled syringe or cartridge, e.g. a cartridge that can be loaded into a device for infusion/injection, e.g. a cartridge for a syringe or an infusion system.
• a vial e.g. a single-dose vial, e.g. a colorless borosilicate (type I) glass vial, e.g. of about 30 mL size, e.g. closed with a bromobutyl rubber stopper (stopper with silicate filler and in
• the dose unit may be provided in a lead shielded container, preferably placed in a plastic sealed container.
• the dose unit may be shipped in a Type A packaging system (according to the corresponding regulations of the International Air Transport Association (IATA) and International Carriage of Dangerous Good by Road (ADR)).
• the Type A packaging is designed to meet the radiological protection requirements.
• the aqueous solutions of the present disclosure may be first dispensed in a vial and then transferred into a syringe.
• the aqueous solutions of the present disclosure may be injected intravenously (IV, by bolus injection or infusion) or intraarterially, or intratumorally.
• the aqueous solutions of the present disclosure may be administered to the patient by slow intravenous push within approximately 1 to 10 minutes (either with a syringe pump or infusion pump or manually), e.g. via an intravenous catheter that is pre-filled with e.g. 0.9% sterile sodium chloride solution.
• the aqueous solutions of the present disclosure may be administered at a dosage/dose of about 7.4 ( ⁇ 10%) GBq (200 ( ⁇ 10%) mCi) every about 6 weeks for up to about 6 doses.
• the dose may be temporarily interrupted (e.g. extending the dosing interval from every about 6 weeks up to every about 7, 8, 9, or 10 weeks), or the dose may be reduced, e.g.
• the Lutetium-177 for the embodiments of the present disclosure may be prepared using two different sources of stable isotopes (either lutetium-176 or ytterbium-176).
• Lutetium-177 prepared using the stable isotope lutetium 176 is also referred to as “carrier added” (c.a., CA) may contain small amounts of long-lived metastable lutetium-177 ( 177m Lu) with a half life of 160.4 days.
• Lutetium-177 prepared using ytterbium-176 is also referred to as “non carrier added” (n.c.a., NCA).
• NCA non carrier added
• both versions of Lutetium-177, CA as well as NCA may be used, preferably without changing the other components qualitatively or quantitatively.
• n.c.a. 177 Lu is used.
• Example 1 Production of a sterile, aqueous concentrated solution of 177 Lu-DOTA- TATE 1.1 Introduction
• the radioactive Drug Substance 177 Lu-DOTA-TATE also referred hereafter as 177 Lu- DOTA0-Tyr 3 -Octreotate is produced as a sterile, aqueous concentrated solution (so-called Mother Solution).
• Drug Substance synthesis steps are performed in a self-contained closed-system synthesis module which is automated and remotely controlled by GMP compliant software and automated monitoring and recording of the process parameters. During each production run of the synthesis module, a single use disposable kit cassette, containing a fluid pathway (tubing), reactor vial and sealed reagent vials is used.
• the synthesis module is protected from manual interventions during the production run.
• the synthesis module is placed in a lead-shielded hot cell providing supply of filtered air.
• the synthesis of the Drug Substance ( 177 Lu-DOTA0-Tyr 3 -Octreotate) and its formulation into the Drug Product ( 177 Lu-DOTA0-Tyr 3 -Octreotate 370 MBq/mL solution for infusion) is part of an automated continuous process which does not allow for isolation and testing of Drug Substance due to its radioactive decay.
• the synthesis of the Drug Substance is carried out using MiniAio (Trasis) kit cassette.
• MiniAio Trasis
• the following flow chart shows the chemistry process for the manufacturing of the Drug Substance in the Grade C Hot Cells at 4 Ci and 8 Ci batch size.
• the labeling (step 7) consists of the chelating of 177Lu into the DOTA moiety of the DOTA- Tyr3-Octreotate peptide.
• the labeling is carried out at 94°C ⁇ 4°C.
• DOTA0-Tyr3-Octreotate is present in a molar excess respect to the 177Lu to ensure acceptable radiochemical labeling yields.
• the chemical reaction for producing the Drug Substance 177Lu-DOTA0-Tyr3-Octreotate is illustrated in the following.
• the formulation, sterilizing filtration and dispensing processes of the Drug Product are carried out in the Grade A Dispensing Isolator.
• the following flow chart shows in the detail the steps for the manufacturing of the Drug Product.
• Step 1c Reaction Buffer Lyophilisate dissolution Before its use in the Drug Substance synthesis, Reaction Buffer Lyophilisate (RBL) is reconstituted by Drug Substance manufacturing site by dissolution with water for injection (WFI) to obtain Reaction Buffer solution. Reconstitution is carried out immediately before the start of the synthesis.
• RBL Reaction Buffer Lyophilisate
• WFI water for injection
• DOTA-Tyr 3 -Octreotate - For 74 GBq batch size (2 Ci batch size): one vial of DOTA-Tyr 3 -Octreotate is reconstituted with 2 mL of WFI using a sterile, disposable syringe. - For 148 GBq batch size (4 Ci batch size): two vials of DOTA-Tyr 3 -Octreotate are reconstituted with 2 mL of WFI per vial. The content of one solubilised DOTA-Tyr 3 -Octreotate vial is transferred into the other one using a sterile disposable syringe, and mixed up in order to obtain one vial containing 4 mL of product.
• Step 5 Installation of starting material on the kit cassette Reaction Buffer solution, WFI and precursors are installed on the corresponding cassette positions according to the synthesis module used. The installations are performed in a Grade C environment.
• Step 6 Transfer of Lu-177 chloride solution, Reaction Buffer solution and DOTA- Tyr 3 -Octreotate solution into the reactor The synthesis is initiated by pushing the “start synthesis” button on the synthesis module PC control software program. The first step of the synthesis consists of the automated transfer of all components needed for the labeling into the cassette reactor. Radioactive and chemical Drug Substance precursors and Reaction Buffer solution are transferred into the reactor in the following order: 1. Lu-177 chloride solution 2. Reaction Buffer solution 3.
• the Lu-177 chloride solution is drawn into the reactor when the valves (positions 5 and 6 of the GE cassette or positions 1 and 2 of the MiniAIO cassette), are opened and negative pressure is applied to the reactor.
• the Lu-177 chloride solution is highly concentrated and therefore incomplete transfer of the solution into the reactor l can impact the labeling yield. For this reason, the Reaction Buffer solution is added to the Lu-177 chloride solution vial before its transfer into the reactor in order to ensure complete transfer of the Lu-177 chloride solution.
• Reaction Buffer is transferred into Lu-177 chloride vial using syringe (right 30 mL syringe 1 for TRACERlab MX synthesis module and 30 mL syringe 2 for MiniAIO synthesis module). From this vial, the solution (Reaction Buffer + Lu-177 residual) is transferred into the reactor by applying negative pressure. The last step to initiate synthesis of the Drug Substance is the transfer of the DOTA-Tyr 3 - Octreotate solution to the reactor. This is automatically performed by negative pressure applied to the reactor.
• DHB gentisic acid (2,5-dihydroxybenzoic acid)
• the labeling consists of the chelating of Lu-177 into the DOTA moiety of the DOTA-Tyr 3 - Octreotate peptide. The labelling is carried out at 94°C ( ⁇ 4°C) for: ⁇ 5 minutes ( ⁇
• Step 8 Transfer and first filtration of Drug Substance (prefiltration)
• 177 Lu-DOTA 0 -Tyr 3 -Octreotate Mother Solution obtained is sterilized a first time using a sterilizing filter connected to the extension sterile cable.
• the 177 Lu-DOTA 0 -Tyr 3 -Octreotate Mother Solution is automatically transferred by positive nitrogen pressure from the synthesis hot- cell (Grade C) into the dispensing isolator Grade A by the extension sterile cable and is collected in an intermediate 30 mL sterile vial.
• a vent filter with a microlance needle is used to equilibrate pressure in the intermediate 30 mL sterile vial.
• the cassette and the reactor are rinsed 3 times with 3 mL of water for injection each time, in order to recover 177 Lu-DOTA 0 -Tyr 3 -Octreotate remaining in the lines.
• the volume of 177 Lu-DOTA 0 -Tyr 3 -Octreotate Mother Solution at the end of the transferring process is: ⁇
• 2 Ci batch size ⁇ 13.0 mL
• 4 Ci batch size ⁇ 19.0 mL
• the volume and the radioactivity of the 177 Lu-DOTA 0 -Tyr 3 -Octreotate Mother Solution are controlled at the end of the synthesis and monitored. The synthesis yield is calculated. 1.13 Results
• Example 2 177Lu-PSMA-617 manufacturing
• MiniAio (Trasis) kit cassette For the kit assembly (under Grade C), follow Figure 2.
• the following flow chart shows the chemistry process for the manufacturing of the Drug Substance in the Grade C Hot Cells.
• the labeling proceeds by chelation of 177Lu into the DOTA moiety of the PSMA- 617.
• the labeling is carried out at 94°C ⁇ 4°C for 5 ⁇ 0.5 minutes.
• DOTA-PSMA is present in a molar excess respect to the 177Lu to ensure acceptable radiochemical labeling yields.
• the chemical reaction for producing the Drug Substance 177Lu-DOTA-PSMA is illustrated in the figure below: Drug product formulation, sterilizing filtration and dispensing are carried out in the Grade A Dispensing Isolator.
• the following flow chart shows in detail the steps for the manufacturing of the Drug Product.
• the dilution solution is prepared by dissolving the appropriate amounts of sodium ascorbate and pentetic acid (DTPA) in water for injection (WFI).
• DTPA pentetic acid
• WFI water for injection
• Reaction buffer solution for 177Lu-PSMA-617 Gentisic acid: 157.5 mg Acetic acid: 120.2 mg Sodium acetate: 164.0 mg
• a batch size can contain 1- 40 customer vials according to the batch size.
• composition of the drug product 177Lu-PSMA-617 solution for injection/infusion per mL of solution is described in the following table.
• 2 includes all water, also the small amounts of water that may be left over from the sterilization process.
• 3 calculated and rounded values.
• the composition of the drug product per single dose taking as reference the minimum (7.5 mL) and the maimum (12.5 mL) filling content is described in the following table.
• 2 includes all water, also the small amounts of water that may be left over from the sterilization process.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Organic Chemistry (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Pharmacology & Pharmacy (AREA)
• Optics & Photonics (AREA)
• Physics & Mathematics (AREA)
• Dispersion Chemistry (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Genetics & Genomics (AREA)
• Zoology (AREA)
• Gastroenterology & Hepatology (AREA)
• Endocrinology (AREA)
• Analytical Chemistry (AREA)
• Toxicology (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Peptides Or Proteins (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (1)

Family

ID=85221934

Family Applications (1)

Country Status (9)

Cited By (2)

Citations (5)

• 2023
  • 2023-02-03 US US18/832,623 patent/US20260053959A1/en active Pending
  • 2023-02-03 JP JP2024532528A patent/JP2025506322A/ja active Pending
  • 2023-02-03 CA CA3235923A patent/CA3235923A1/en active Pending
  • 2023-02-03 IL IL313964A patent/IL313964A/en unknown
  • 2023-02-03 KR KR1020247028693A patent/KR20240146015A/ko active Pending
  • 2023-02-03 CN CN202380014200.XA patent/CN118159303A/zh active Pending
  • 2023-02-03 EP EP23704451.6A patent/EP4472678A1/en active Pending
  • 2023-02-03 WO PCT/IB2023/050982 patent/WO2023148680A1/en not_active Ceased
  • 2023-02-04 TW TW112104011A patent/TW202342112A/zh unknown

Patent Citations (5)

Non-Patent Citations (8)

Also Published As

Similar Documents

Legal Events