EP4168173A1 - Mikrowellenvorrichtung zur schnellen markierung von in kit-formulierten radiopharmazeutika - Google Patents
Mikrowellenvorrichtung zur schnellen markierung von in kit-formulierten radiopharmazeutikaInfo
- Publication number
- EP4168173A1 EP4168173A1 EP20736459.7A EP20736459A EP4168173A1 EP 4168173 A1 EP4168173 A1 EP 4168173A1 EP 20736459 A EP20736459 A EP 20736459A EP 4168173 A1 EP4168173 A1 EP 4168173A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- precursor
- acid
- generator
- molecules
- gallium
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
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
- A61K51/0402—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
- A61K51/0497—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
- A61K51/08—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
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22B—PRODUCTION AND REFINING OF METALS; PRETREATMENT OF RAW MATERIALS
- C22B3/00—Extraction of metal compounds from ores or concentrates by wet processes
- C22B3/20—Treatment or purification of solutions, e.g. obtained by leaching
- C22B3/22—Treatment or purification of solutions, e.g. obtained by leaching by physical processes, e.g. by filtration, by magnetic means, or by thermal decomposition
- C22B3/24—Treatment or purification of solutions, e.g. obtained by leaching by physical processes, e.g. by filtration, by magnetic means, or by thermal decomposition by adsorption on solid substances, e.g. by extraction with solid resins
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22B—PRODUCTION AND REFINING OF METALS; PRETREATMENT OF RAW MATERIALS
- C22B3/00—Extraction of metal compounds from ores or concentrates by wet processes
- C22B3/20—Treatment or purification of solutions, e.g. obtained by leaching
- C22B3/42—Treatment or purification of solutions, e.g. obtained by leaching by ion-exchange extraction
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22B—PRODUCTION AND REFINING OF METALS; PRETREATMENT OF RAW MATERIALS
- C22B58/00—Obtaining gallium or indium
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
- G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
- G21G1/0005—Isotope delivery systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P10/00—Technologies related to metal processing
- Y02P10/20—Recycling
Definitions
- the present invention relates to a microwave device specifically designed for radiopharmaceutical applications and able to enhance the commonly used labelling conditions of gallium-68.
- it relates to a process in which, thanks to this device, the labelling of bioconjugates compounds with gallium-68, obtained from whatever the current in-use 68 Ge/ 68 Ga generators, is performed directly, without pre purification, in a single vessel and in a few seconds.
- Such 68 Ga-labelled radiopharmaceuticals can be used for diagnosis and follow up of neoplastic diseases, inflammatory pathologies and/or metabolic disorders.
- Radiopharmaceuticals or radiotracers are molecules used in the diagnostic imaging field, for example in positron emission tomography (PET) and in single photon emission computed tomography (SPECT) for diagnosing the presence of diseases, in particular tumours. Radiotracers can also be used for therapeutic purpose in procedures known as peptide receptor radionuclide therapy (PRRT) or immuno-mediated radiotherapy (IRT) depending on the radionuclide associated to the chemical structure.
- PRRT peptide receptor radionuclide therapy
- IRT immuno-mediated radiotherapy
- a radiotracer consists in a molecule covalently bound to a chelating agent able to form stable coordination compounds with a radioactive metal isotope, for example gallium-68, lutetium-177 or technetium-99m. This molecule shows high affinity for a specific molecular receptor which, for example, is over-expressed by tumour cells.
- a radiotracer consists also of a molecule following a determinate metabolic pathways, enhanced or in whatever way modified in tumours or other pathologies, covalently bond to a radioactive isotope, for example fluorine-18.
- a radiotracer also consists in a coordination compound where the complex formed by a ligand and a radioactive metal, for example technetium-99m, is a molecule whose metabolic pathway and accumulation is modified by physiological conditions like disease.
- a radioactive metal for example technetium-99m
- the PET technique has numerous advantages with respect to the SPECT technique in terms of spatial resolution and sensitivity. For this reason, positron- emitting radionuclides are normally preferred over g-emitting radionuclides for labelling peptides or other molecules for diagnostic purposes.
- gallium-68 is one of the most commonly used since it has a positron energy and a half-life suitable for applications in diagnostic nuclear medicine. Furthermore, gallium-68 can be obtained by commercially available 68 Ge / 68 Ga generators in a chemical form and purity suitable for labelling small molecules and, in particular, peptides.
- Some successful applications of gallium-68 are in the labelling of somatostatin analogues for the diagnosis of neuroendocrine tumours high expressing somatostatin receptors.
- the high affinity of the chemical structure for these receptors allows the radiotracer to accumulate in tumour cells.
- the most commonly used somatostatin derivatives for these applications are TOC, TATE and NOC peptide bound to a proper chelator able to complex metal radionuclides.
- Other successful 68 Ga-labelled radiopharmaceuticals are, for instance, the prostate specific membrane antigen (PSMA) inhibitors that are clinically used for the diagnosis and follow-up of prostate cancer.
- PSMA prostate specific membrane antigen
- the most commonly used labelled molecules for this application are: [ 68 Ga]Ga-PSMA-11 , [ 68 Ga]Ga-PSMA-617 and [ 68 Ga]Ga-THP-PSMA.
- the most common chelator for gallium-68 used in clinic are 1 ,4,7,10-tetraacetic acid-1 ,4,7,10- tetraazacyclododecane (DOTA) and N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'- diacetic acid (FIBED-CC), but many other ligands have been studied and are commonly used in medical research.
- kits for labelling are generally intended as a pharmaceutical formulation of one or more glass vessels that contain not-radioactive precursors and excipients. These formulations can be stored in the proper conditions and used offhand when needed.
- a kit is built in order to allow the preparation of a radiotracer by direct addition of a solution of gallium-68 to the vessel containing the precursor. Normally, the reactions take place after some minutes of strong heating at 95°C or simple stirring at RT, depending on the precursor.
- the use of kits allows an easier preparation of radiopharmaceuticals for routine-use in hospitals and normally spares synthetic steps such as processing (purification and concentration) of 68 Ge / 68 Ga generator eluate as well as the purification post-labelling.
- kits for the labelling with gallium-68 of somatostatin analogues DOTATOC and DOTATATE are approved for diagnosis of gastroentero-pancreatic neuroendocrine tumours (GEP-NET) expressing somatostatin receptors.
- GEP-NET gastroentero-pancreatic neuroendocrine tumours
- kits are generally designed for a procedure starting from eluates provided by a single commercial generator (GalliaPharm 68 Ge / 68 Ga generator, Ecker and Ziegler supplier, since it was the first 68 Ge / 68 Ga generator to obtain the marketing authorization).
- this generator the whole procedure for elution and subsequent labelling ranges from 15 to 20 minutes with a consequent yield around 81 - 85% and a final declared radiopharmaceutical purity > 91%.
- Adapting the process to other commercial generators such as the GalliAd, IRE-Elit supplier, the second generator to obtain the marketing authorization
- Radiopharmaceutical synthesis is a close field with peculiar and specific features. Usually, reactions are chemically simple but performed in precise ranges of volume, media and conditions. For this reason, the real potential of the microwaves specifically for this field is not fully unleashed so far.
- One object of the invention is to provide a microwave device specifically designed for the labelling of radiopharmaceuticals.
- the microwave device has the function to activate and speed up the reaction in comparison to the commonly used way of heating or room environment stirring.
- the words “microwave activation”, “microwaves promotion” and synonymous thereof are always referred to a radiolabelling reaction aimed to produce a radiopharmaceutical for clinical use.
- a radiolabelling reaction is considered “activated” or “promoted” when its yield is > 99 % and the product of the reaction has a radiochemical purity > 99 %.
- the device is built for the labelling of kits where kit is intended as vessel/s containing a not radioactive precursor and excipients (buffer, neutralizing agents, stabilizers) to which a solution containing a radioactive radionuclide in a suitable chemical form is added for obtaining a radiotracer.
- kit is intended as vessel/s containing a not radioactive precursor and excipients (buffer, neutralizing agents, stabilizers) to which a solution containing a radioactive radionuclide in a suitable chemical form is added for obtaining a radiotracer.
- the device includes a microwave source, preferably a solid state generator, operating within ISM bands, like the one centred on 2.45 GHz, that is connected through a coaxial cable to a single mode cavity.
- a microwave source preferably a solid state generator
- ISM bands like the one centred on 2.45 GHz
- the model geometry is designed for focusing the microwaves action precisely in the housing where the vessel content is positioned in the upper side of the device.
- a technical sketch of the device is shown in figure 1 [Technical sketch of the single mode cavity].
- the reflection coefficient value (i.e. an indication of the energy efficiency of the process of microwave heating) is adjusted by the presence of a stub inside the cavity.
- the lowest possible value is optimized for the geometries of the vessels normally used for radiopharmaceuticals in-kit preparation and for the solution volumes contained in the vessels.
- the reflection coefficient value is optimized as well for the relative permittivity of the mixtures obtained after the addition of all the reagents necessary for the formulation of this kind of radiopharmaceuticals.
- the dependence of the reflection coefficient value (S11) on the frequency (GHz) applied for two shapes representing vessels used for the radiolabelling, is shown in figure 2 [dependence of the reflection coefficient value (S11) on the frequency applied (GHz) for a 10 ml vessel (A) and for a 30 ml vessel (B)].
- the system is designed to accommodate, in a dedicated housing, 1 or more sealed glass vessels with different geometry which internal capacity ranges from 10 to 30 ml.
- the microwave device is used with a single 10 ml or 25 ml vessel.
- the vessels can be inserted in the housing from above, sliding through a circular opening in the top of the shell and so as the aluminium ferrule is maintained outside the applicator, i.e. the region of space where microwave-matter interaction occurs. After the reaction, the vessels can be easily extracted using a telescopic tong through the same way.
- the system is projected to promote the reactions of different kits containing different precursors and excipients.
- the relative permittivity of the media formed by the addition of precursor, excipient and radionuclide solutions has been computed in order to optimize the effect of the microwave promotion within the described applicator.
- the magnitude of microwaves converted into heat in the load can be measurably influenced by the relative permittivity of the reagent solution itself.
- Suitable promotion happens when the real part of the relative permittivity (s’) of the mixtures obtained after the addition of all the reagents ranges preferably from 60 to 100, most preferably from 66 to 81, and the imaginary part of the relative permittivity (s ) ranges preferably from 5 to 25, most preferably from 8 to 21 at room temperature.
- Suitable microwaves promotion is activated for contents of the vessels comprised between a volume from 1 to 30 ml. Most preferably, when the volume is comprised from 1.1 to 5 ml.
- suitably microwave activation is carried out at 80 to 120 W, preferably at 90 to 110 W, particularly preferably at about 100 W for such load volumes.
- Suitable microwave activation times ranges from 10s to 90s, preferably from 30s to 60s, particularly preferably 30s in case the aforementioned output power is used.
- the reflected energy ranges preferably from 10 to 40 W, most preferably from 15 to 35 W, to minimize power losses.
- the radionuclide is gallium-68 and it is obtained by eluting a 68 Ge / 68 Ga generator.
- Such generators are known in the art (see for instance references [6,7]) and are commercially available from many suppliers.
- 68 Ge is loaded onto a column consisting of organic resin or an inorganic metal oxide like tin dioxide, aluminium dioxide, zirconium dioxide or titanium dioxide or organic resins comprising phenolic hydroxyl groups like as pyrogallol (U.S. Pat. No. 4.264,468) .
- the gallium-68 solution used with the microwave device described herein is obtained by a 68 Ge/ 68 Ga generator comprising a matrix of titanium dioxide or pyrogallol.
- Gallium-68 is obtained by eluting a 68 Ge/ 68 Ga generator with a solution of hydrochloric acid.
- concentration and the amount of the aqueous HCI used to elute the whole amount of gallium-68 depends on the column material and it follows the indication of the company supplying the device.
- 0.05 to 5 M HCI is used for the elution of gallium-68.
- gallium-68 is eluted using 0.05 to 0.1 M HCI, preferably about 0.1 M HCI.
- the volume of the HCI used for the elution ranges from 1 ml to 10 ml, preferably from 1.1 ml to 5 ml of HCI.
- gallium-68 is eluted with 2.2 ml to 10 ml of HCI 0.05 M. In all cases, gallium-68 is eluted in the [ 68 Ga]Ga 3+ cationic form.
- the device is assumed to label in one step the whole 68 Ge/ 68 Ga generator eluate without none pre- or post-purification. Labelling of fractions of the eluate is also possible between the indicated ranges of volume.
- the whole volume of the generator eluate containing gallium-68 is added directly, without purification, to a mixture comprising a precursor tethered to a chelator and a neutralising agent.
- a mixture comprising a precursor tethered to a chelator and a neutralising agent.
- the mixture is a lyophilized powder.
- pH of the reaction ranges from 3 to 5.
- the neutralizing agent is salt of a weak organic acid and the precursor is a molecule with a biological affinity for particular receptors or for a particular metabolism. Said molecule is bound to a proper bifunctional chelator.
- Preferably neutralising agent is selected from an alkaline or alkaline-earth salt of formic acid, preferably a sodium or potassium salt of formic acid, or an alkaline or alkaline-earth salt of ascorbic acid, preferably a sodium or potassium salt of ascorbic acid, or an alkaline or alkaline-earth salt of acetic acid, preferably a sodium or potassium salt of acetic acid, or a mono-substituted alkaline or alkaline-earth salt of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) preferably a sodium or potassium salt thereof.
- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- Precursor is preferably selected from the group consisting of: prostate-specific membrane antigen (PSMA) inhibitors, somatostatin analogues, preferably Tyr3- octreotide (TOC), -octreotate (TATE) and -1-Nal3-octreotide NOC, molecules having affinity for the VEGF receptors, bombesin analogues, molecules having affinity for the GRP receptors, molecules having affinity for the estrogen receptors, molecules having affinity for the integrin receptors (peptides RDG a( ⁇ /)b(3) and a( ⁇ /)b(3)), molecules involved in bone metabolism (diphosphonates), molecules having affinity for the chemokine receptors (CXCR4), molecules having affinity for the cholecystokinin receptor (CCK) and fibroblast activated protein inhibitors (FAPI).
- PSMA prostate-specific membrane antigen
- TOC Tyr3- octreotide
- TATE -octreotate
- NOC
- Bifunctional chelator is preferably selected from the group consisting of: 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), 1,4,7- triazacyclononane-1,4,7- triacetic acid (NOTA), 3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-1(15),11 ,13-triene-3,6,9-triacetic acid (PCTA), N,N'- Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBEDD), 6- [Bis(carboxymethyl)amino]-1 ,4-bis(carboxyrnethyl)-6-methyl-1 ,4-diazepane (AAZTA), tris-hydroxypyridinone (THP), 1 ,2-[[6-carboxypyridin-2-yl]methylamino]ethane) (DEDPA), 1
- said precursor and chelator is selected from: DOTA-TOC, DOTA-TATE, DOTA-NOC, DOTA-peptide, DOTA-PSMA, HBEDD-PSMA, DOTA- FAPI.
- the vessel containing the precursor/neutralizing agent is already inside the resonant cavity of the device and the eluate is added directly from the generator through the elution procedure indicated by the generator supplier.
- the generator is eluted inside an empty vessel inserted in the resonant cavity and the mixture containing the precursor/neutralizing agent, dissolved elsewhere, is added afterwards.
- the mixture of eluate, precursor and neutralizing agent solutions (in any order of addition) is obtained in a vessel elsewhere and then this vessel is put in the resonant cavity.
- the total volume of the reaction ranges preferably from 1 to 30 ml.
- the device is then switched on for promoting the reaction of labelling.
- the power on consist just in an electrical activation.
- the irradiation parameters are already optimized depending on the precursor and on the vessel geometry. No further intervention is required from the operator.
- a commercial 1850 MBq 68 Ge/ 68 Ga Galli-Ad generator (IRE-Elit) is eluted with 1.1 ml of HCI 0.1 M directly in a commercial vessel containing 107 mg of neutralizing agent (sodium ascorbate) and 25 ug of precursor (PSMA-11).
- the vessel is inserted in the microwave reactor object of this invention and it is activated for 60 second at 100 W power level, resulting in a reflected power of 30-40 W.
- the vessel is extracted, diluted with 9 ml of saline solution and stored in a shielding.
- a commercial 1850 MBq 68 Ge/ 68 Ga GalliaPharm generator (EZAG) is eluted with 5 ml of HCI 0.1 M directly in a commercial vessel containing 42 mg of neutralizing agent (sodium formate) and 50 ug of precursor (DOTATOC).
- the vessel is inserted in the microwave reactor object of this invention and activated for 90s at 100 W power level, resulting in a reflected power of 15-20 W.
- the vessel is extracted, diluted with 9 ml of saline solution and stored in a shielding. An aliquot is withdraw for the quality control performed by UHPLC by following the method prescribed in the European Pharmacopeia for [ 68 Ga]Ga-DOTATOC preparations for injection.. Results: Radiochemical yield 99%. Radiochemical Purity 99% (figure 4 - paradigmatic UHPLC chromatogram (radiochemical detector) of a [ 68 Ga]Ga-DOTATOC preparation using the microwave reactor object of this invention).
- a commercial 1850 MBq 68 Ge/ 68 Ga GalliaPharm generator (EZAG) is eluted with 5 ml of HCI 0.1 M directly in a commercial vessel. Then a 300 uL solution containing 42 mg of neutralizing agent (sodium formate) and 25 ug of precursor (PSMA-11) is added. The vessel is inserted in the microwave reactor object of this invention and activated for 30s at 100 W power level, resulting in a reflected power of 15-20 W. The vessel is extracted, diluted with 9 ml of saline solution and stored in a shielding.
- neutralizing agent sodium formate
- PSMA-11 precursor
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IT2020/000039 WO2021234741A1 (en) | 2020-05-18 | 2020-05-18 | Microwave device for the rapid labelling of in kit-formulated radiopharmaceuticals |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4168173A1 true EP4168173A1 (de) | 2023-04-26 |
Family
ID=71452526
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP20736459.7A Pending EP4168173A1 (de) | 2020-05-18 | 2020-05-18 | Mikrowellenvorrichtung zur schnellen markierung von in kit-formulierten radiopharmazeutika |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP4168173A1 (de) |
WO (1) | WO2021234741A1 (de) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4264468A (en) | 1979-01-08 | 1981-04-28 | Massachusetts Institute Of Technology | Generator for gallium-68 and compositions obtained therefrom |
US20060188441A1 (en) | 2005-02-22 | 2006-08-24 | Vladimir Tolmachev | Radiolabeled gallium complexes, methods for synthesis and use for PET imaging of EGFR expression in malignant tumors |
-
2020
- 2020-05-18 EP EP20736459.7A patent/EP4168173A1/de active Pending
- 2020-05-18 WO PCT/IT2020/000039 patent/WO2021234741A1/en unknown
Also Published As
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WO2021234741A1 (en) | 2021-11-25 |
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