WO2017144959A1

WO2017144959A1 - Apparatus for labelling molecules with gallium-68

Info

Publication number: WO2017144959A1
Application number: PCT/IB2016/053275
Authority: WO
Inventors: Paulo ROBERTO WALTER FERREIRA; Caroline MACHADO DARTORA; Jaime CRISTIANO SCHREINER; Maicon CARLOS PELISSARO PASIN; Ricardo GALILEO ANELE FILHO; Rodrigo SANTOS KALIKOSKI; Edison MARTINS DA SILVA JÚNIOR; Ivan MIRANDA; Marcelo SARAIVA DOS SANTOS; Alice FIALHO VIANA; Patrícia COELHO LAMACHIA MADKE; Rafael RIBEIRO MADKE; Salus CARDOSO VIDAL; Patrícia MACHADO NABINGER
Original assignee: Serviço Nacional De Aprendizagem Industrial - Senai.; Bhio Supply Indústria E Comércio De Equipamentos Médicos Ltda; Mjm Produtos Farmaceuticos E De Radioproteção Ltda
Priority date: 2016-02-23
Filing date: 2016-06-03
Publication date: 2017-08-31

Abstract

An apparatus is described for labelling molecules with gallium-68, for eluting all gallium-68 generators presently available on the market, by means of a single, single-use labelling circuit (CM) for purifying radioactive material, in order to obtain radioactive materials without any metal contaminants, such as Fe³⁺ and Zn²⁺, which could be detrimental to molecule labelling, purification being carried out in that the gallium-68 eluate is passed through a chromatography column and a sterilising filtration system for the radiopharmaceutical labelled with gallium-68, so as to render the radiopharmaceutical sterile and apyrogenic.

Description

Molecule Marking Equipment with

Gallium-68

FIELD OF INVENTION

[01] The present invention describes an apparatus for labeling molecules with Gallium-68. More specifically, it comprises equipment that elutes all currently available Gallium-68 generators via the same circuit to label the radiopharmaceutical with the Gallium-68 radioisotope. BACKGROUND OF THE INVENTION

[02] Nuclear medicine has been booming after the development of PositronEmissionTomography (PET) equipment. The possibility of hybrid equipment (PET or SPECT with computed tomography - SPECT / CT, PET / CT - or with magnetic resonance - SPECT / MRI, PET / MRI) has also been supporting the growing use of diagnostic functional imaging.

[03] In Brazil, there are currently about 418 nuclear medicine services, according to data from the National Nuclear Energy Commission (CNEN). Of these, 84 have PET equipment, most of which are located in the state of São Paulo. Compared to SPECT systems, PET equipment provides higher accuracy and better sensitivity images. However, positron-emitting radionuclides have, as a particular feature, a short half-life (less than 02 hours), most of which are produced in cyclotrons, whereas single photon-emitting radionuclides are produced through reactors and are distributed to generators, taking half a time. - medium to long life (more than 04 hours).

[04] Mostly, positron emitters are produced in cyclotrons. Because the emitter's half-life (t _1/2 ) is short, as in the case of fluorine-18 (\ _V2 = 1 10 minutes), carbon-1 1 (ti _{/ 2} = 20 minutes) and oxygen-15 (ti _{/ 2} = 2 minutes), the examination sites need to be close to the cyclotron.

[05] Gallium-68 is a generator-produced positron emitter. The generator consists of Germanium-68 ( ⁶⁸ Ge) (t1 _{/ 2} = 270.95 days) which decays to Gallium-68 (t _1/2 = 68 minutes), having about 99% of its maximum activity recovered in 7 hours after the first elution. However, Gallium-68 is eluted from the generators with 0.05-0.1 M hydrochloric acid, resulting in a solution of pH less than 2 of Gallium-68 chloride, which cannot be injected directly into the patient, requiring dilution, concentration and purification steps.

[06] In order to be injected into patients, Gallium-68 must meet certain criteria such as: labeling efficiency greater than or equal to 95%, Iron impurities must be insignificant for gallium-68 drug labeling (maximum 10μg / GBq), Zinc-68 impurity (from Gallium-68 decay) maximum ^ g / GBq, Germanium-68 impurities in the final product shall not exceed 0.001% of total radioactivity, energy photons between 0.51 1 MeV and 1,077 MeV in gamma ray spectrometry, sterility, being pyrogen-free and within Good Manipulation Practices according to the National Health Surveillance Agency (ANVISA) standards. This requires a series of steps for a high quality end product.

[07] State-of-the-art radiopharmaceuticals are mostly unshielded, requiring the use of a hot cell, which is characterized by shielded equipment to safely handle radioactive isotopes. This kind of This equipment is present only in cyclotron radioisotope production sites and is not part of existing radiopharmaceutical equipment, given the high cost and size.

[08] The prior art provides various documents describing radionuclide molecule labeling equipment.

[09] DE202012000944 claims a semi-automated shielded Gallium-68 synthesis apparatus adapted to receive a lightweight, small compact design radioactive isotope generator which can be loaded and placed on a table.

DE102004057225 describes a method for obtaining Gallium-68 eluate from a Germanium-68 / Gallium-68 generator containing Gallium-68 in ionic form, fed directly by a cationic column which will perform chemical purification and for combination with a labeling covalently linked to a peptide or protein to form a radiopharmaceutical.

US20080035542 describes an automated system for the purification of radioisotopes and labeling of radiopharmaceuticals. To use radioisotopes produced in generators, synthesis is performed automatically using a replaceable cassette system for easy replacement and kits for use with the system.

DE202010017082 describes a device for marking molecules under sterile conditions so that their components are arranged in an armored housing. The device contains at least one reactor for labeling the molecule with radioactive material, this reactor having at least a reactor charging port, a vent valve for generating positive and negative pressure in the reactor and an outlet means for transporting the radionuclide labeled molecule, such as containing at least one sterile collection vial to collect the final material.

US20080277350 describes a method and device for chemically and radiochemically isolating Gallium-68 for labeling a drug. The method consists in the use of a cationic column for the absorption of Gallium-68, purification of the eluate occurs, as Germanium-68 is not adsorbed and contamination by Germanium-68 is reduced to values less than 10 ^" ⁸ %. Purification continues with acidic solutions so that chemical contamination by Fe (lll), Zn (ll) and Ti0 ₂ is eluted from the cationic column.

US20070027307 describes a method for producing Gallium-68 complexes for reaction with ⁶⁸ Ga ^{+ 3} chelating agents using the microwave activation technique.

WO2005123144 is a system and method for the automated synthesis of Gallium-68 for the production of radiopharmacological agents. In the system, a generator is provided that supplies a mixture of Gallium-68 with hydrochloric acid (HCI). A heater initiates the evaporative hydrochloric acid removal process from the mixture, resulting in purified Gallium-68.

[016] CA2520176 describes a method for obtaining Gallium-68 from a ⁶⁸ Ge / ⁶⁸ Ga generator with Ti0 ₂ matrix and a method for obtaining Gallium-68 radiolabeled complexes. The system contains an anionic column composed of HCO ^" ³ ions (which is a strong anionic column composed of quartenary amine functional groups) for the elution of Gallium-68. According to the method, the column is eluted with 0.05 at 0.1 M HCI and Water is then used to elute Gallium-68 from the anionic column. The method for labeling complexes with Gallium-68 is carried out by atom-donating macrocyclic chelating agent, which is a bifunctional agent comprising a targeting vector for the group of selected organic molecules. The reaction is carried out through microwave activation. Also disclosed is a ⁶⁸ Ga preparation kit of a ⁶⁸ Ge / ⁶⁸ Ga generator comprising hermetically sealed, aseptic vials of HCI and water for elution of the anionic matrix and column and a bifunctional chelating agent for the production and radiolabeling of tracers. PET.

CN104321084 describes a radiopharmaceutical preparation kit comprising a cation exchange column, a reaction vial containing the lyophilized labeling precursor, a dissolution vial containing a solvent, such as a sterile aqueous acetic acid and acid solution hydrochloric acid, an elution vial comprising saline (NaCl) and hydrochloric acid in sterile solutions as buffer solutions.

US20130310537 describes a method and kit for preparing radiopharmaceuticals. The method comprises elution steps of the ⁶⁸ Ge / ⁶⁸ Ga generator using HCI as eluent obtaining a Gallium-68 eluate from the generator, a cationic column where Gallium-68 will be collected, separation of the eluent used, eluting Gallium-68 from the cationic column with a solution comprising sodium chloride and HCl and adding the eluate resulting in an aqueous precursor mixture for the drug labeling steps from a reaction.

[019] US20120107175 describes a system composed of small subsystems or modules for chemical synthesis. for the preparation of small quantities of chemicals, particularly radiopharmaceuticals. The module consists of a plug-and-play modules system that allows the operator to manually reset touchandsee for radiochemical synthesis and radiolabelling that can be remotely controlled by the operator. The system consists of a solid phase extraction column for multi-step reaction coordination, purification and quality control and a vial that supports high pressures. A remote control is used so that the operator can operate equipment inside a hot cell. The plug-and-play system allows the combination of different configurations to perform different syntheses. Examples of modules that can be incorporated into the system are reagent storage, cartridge purification module, microwave reaction module, external quality control / analysis / purification, aliquot module, drying module, concentration module, radiation counting module and capillary reactor module.

[020] US20040028573 describes a chemical reagent-based radiopharmaceutical synthesis device containing vials, reaction vials and reaction compartments (preferably flexible tubes) as well as mechanical controls for transfer between vials on a monitor by mechanically controlling these transfers. The device is characterized in that it contains a fixed module including mechanical means, a removable and disposable module containing no mechanical part, the fixed module being essentially in the form of a support, on which the transfer means between the vials and the tubes are arranged. reaction compartments. [021] The document US7728310 describes a method for the chemical separation of Ge ⁶⁸ Ga ⁶⁸ free from impurities by using an eluent citric acid thus eluted gallium-68 in the form of gallium citrate. Thereafter, this eluent is bound to a mixing space of hydrochloric acid, thus gallium citrate converting to gallium tetrachloride. A second resin column is connected to the retention space outlet being transferred with an eluent consisting only of water or weak buffer for eluting the ⁶⁸ Ga radioisotope for subsequent labeling of molecules and a source with a third eluent comprising a chelator. determined pH connected to the second resin column for subsequent output of a Gallium-68 chelator for imaging applications. The apparatus for the generator contains shielding over the columns to limit radiation exposure.

US20100256331 describes a method for producing ⁶⁸ Ga labeled complexes at room temperature for use with diagnostic agents. The method for producing a ⁶⁸ Ga ^{+ 3} labeled complex with a chelating agent consists of a macrocyclic bifunctional chelating agent, which chelating agent has a target vector selected from a peptide or oligopeptide. The reaction is performed between 20 ^S C and 25 ^S C with microwave activation in less than 10 minutes. The ⁶⁸ Ga ⁺³ is obtained by contacting the eluate with the ⁶⁸ Ge / ⁶⁸ Ga generator column with an anionic column that has HC0 ₃ with ions and eluting Gallium-68 ^{+3 from} this column, being the generator column matrix of titanium dioxide.

[023] The state of the art basically describes two generator models: with titanium dioxide adsorbent column (Ti0 ₂ ) or with silica matrix. For the elution of the adsorbent column and the removal of Gallium-68 generator, all generators need to be eluted with hydrochloric acid at specific concentrations for each type of generator. For column adsorption a low pH is required due to Gallium-68 affinity issues. The higher the pH, the higher the Germanium-68 drag will be. Due to this low pH, purification and / or concentration of the eluate prior to administration to the patient is required. Currently, each equipment has its own marking circuit to elute the Germanium 68 and Gallium-68 generators.

[024] Accordingly, the object of the present invention is a device for marking gallium-68 molecules capable of eluting all commercially available gallium-68 generators through the same single-use marking circuit. of plastic components that are used for the synthesis / purification of Gallium-68, featuring a cabinet with or without lead shielding.

SUMMARY

It is a feature of the invention that an apparatus for labeling molecules with Gallium-68 is adaptable to various types of synthesis, which is dependent on the generator column matrix of the radioactive element with which it is worked.

[026] It is a feature of the invention that an apparatus for marking gallium-68 molecules can have a shielded or unshielded enclosure, depending on the needs of the service.

It is a feature of the invention that Gallium-68 molecule marking equipment is provided with a disposable marking circuit which is easy to handle and fits into the equipment cabinet and can be provided as a cassette to be mounted by the operator as required. generator specific configuration. [028] It is a feature of the invention that an apparatus for marking molecules with Gallium-68 is provided with a marking circuit that allows the purification of radioactive material so that it has no metallic contaminants such as Fe ³⁺ and Zn ^2+. may impair the marking of the molecule, said purification occurring by passing the Gallium-68 eluate through a chromatographic column.

[029] It is a feature of the invention an apparatus for labeling molecules with Gallium-68 which allows the labeling of several radiopharmaceuticals using the same labeling circuit.

[030] It is a feature of the invention an apparatus for labeling gallium-68 molecules which features a sterile gallium-68 labeled radiopharmaceutical filtration system such that said radiopharmaceutical is sterile and pyrogen-free.

BRIEF DESCRIPTION OF THE FIGURES

[031] Figure 1A shows the perspective view of the Gallium-68 Molecule Marking Equipment cabinet and Figure 1B shows the open cabinet showing the location of the flat matrix placement of the marking circuit.

[2] Figure 2 shows the schematic circuit representation of the gallium-68 molecule marking equipment.

Figure 3 shows the flat matrix of the marking circuit, showing the niches for positioning the circuit components.

Figure 4A shows the perspective view of the needle moving device positioned on the flat die of the marking circuit and Figure 4B shows the vertical displacement of the needles.

DETAILED DESCRIPTION OF THE INVENTION

[035] The equipment for marking molecules with Gallium-68, The object of the present invention comprises a portable cabinet (200) provided with an electronic control circuit that performs the synthesis-related routines of the radioisotope labeled with the Gallium-68 radioisotope, in manual, semiautomatic and automatic circuit modes. (CM) labeling molecules.

[036] The electronic control circuit comprises a power supply, an interface board, a processing board, a keyed interface panel for operating the electrical system, the heating system and the selection of operating mode (manual, automatic or automatic), adjustment of the position of the valves (V) in the marking circuit (CM), operating warnings (connected device, heating) and actuation of the actuators (pneumatic valves and servo motors).

[037] In the interface panel the operator selects the radionuclide generator type, reactor temperature (R) and system control means and selections for semi-automated marking of molecules with Gallium-68.

[038] The control module controls valves (V) and peristaltic pumps (B) by servo motors to promote the ingress of compressed air, nitrogen or other gallium synthesis fluids. -68 on a marking circuit (CM).

The marking circuit (CM) comprises a flat die (100) disposed in the inner region of the cabinet of the molecule marking equipment (200), said die (100) provided with niches (110) for the fitting of the components. (CM) which are interconnected to pipes (T) and valves (V), with opening and closing control effected by the servo motors.

[040] For the synthesis of radiopharmaceuticals labeled with the Gallium-68 radioisotope, the marking circuit (CM) features a gallium-68 elution (G) disposed within or outside the cabinet (200), said gallium-68 elution generator (G) which receives a determined volume of hydrochloric acid (HCI) through a valve (V) ) through a pipe (T1). In the Gallium-68 (G) elution generator, due to the pH of the hydrochloric acid (HCI), the Gallium-68 decayed from Germanium-68 is dragged, and the parent radionuclide (Germanium-68) is retained in a chromatographic column (Col).

Gallium-68 eluate is routed from the Gallium-68 elution generator (G) to a container (C) through a pipe (T2) provided with a valve (V).

[042] The container (C) receives through a pipe (T3) a mixture of ascorbic acid (C ₆ H ₈ 0 ₆ ) and sodium chloride (NaCl) previously adjusted in a valve (V).

[043] A chromatographic column (Col) is connected directly to the container (C) through a tubing (T4), so that the Gallium-68 eluate deposited in the container (C) is purified on the chromatographic column (Col) for retention. radioactive material and extraction of metallic impurities, returning to the container (C) through a closed circuit controlled by valves (V).

Metal contaminants trapped in the chromatographic column (Col) are routed through a tubing (T5) to a disposal container (Cd) which forwards the residue to a microbiological filter (Fm).

[045] When the electronic control circuit identifies the purification of the Gallium-68 eluate at predetermined system times, the Gallium-68 eluate is released to a pipeline (T6) where it flows into a marking reactor. of molecules (R), where it is kept for about 6 minutes at a temperature of 125 ° C.

[046] The molecule-marking reactor (R) receives, through a pipe (T7), a previously adjusted mixture of ethanol (E) and sodium chloride (NaCl), and through a pipe (T7a) a peptide (Pep) which mixes with ethanol (E) and sodium chloride ( NaCl), said mixture can be filtered in the microbiological filter (Fm), to be released in the reactor (R) through a pipe (T7b).

[047] In a pipe (T7c) connected to the pipe (T7b) by a valve (V), a silica-based high-hydrophobic bonded phase cartridge (CF) is provided for the purification of the radiolabeled molecule from the reactor (R). , the impurities being directed to the disposal container (Cd) and the radiolabeled molecule directed to a microbiological filter (Fm) and then to a final product container (Cpf).

The final product container (Cpf) containing the Gallium-68 radiolabeled molecule is positioned in a front niche (11) of the flat die (100).

[049] As shown in Figure 4A, on the flat die (100) is coupled a needle moving device (300) which promotes the vertical movement of needles (310) between a retracted position, allowing the operator to connect / disconnect at least a needle (310) and remove at least one nozzle end product container (Cpf) positioned in the niche (11) disposed at the front portion of the flat die (100), or an forward position, where at least one needle (310) ) is introduced into at least one final product container (Cpf).

[050] The needle-moving device (300) has a vertically displaceable base (301) in vertical guides (302) by spring compression (303) so that needles (310) disposed at the ends of the base (301) enter the final product container (Cpf) in order to route the labeled molecule deposited in the end product container (Cpf) and impurities retained in the disposal container (Cd) for specific containers to be removed from the interior of the enclosure (200) without the risk of accident or contact with radioactive material.

[051] For the operation of the gallium-68 molecule marking equipment, the operator activates the electrical system from which the reactor heating (R) begins to reach the temperature set in the electronic control circuit. The operator then selects the operating mode (manual, semi-automatic or automatic).

[052] In manual mode, the operator follows procedures as established, performing time control by means of a stopwatch or timer by operating the pneumatic valve (V) and the marking circuit servo motors (CM).

[053] In semiautomatic mode, the timing and opening of the valves (V) is performed through the processor, where each synthesis step is informed on the panel, indicating to the operator which next phase to perform the functions. drives.

[054] In automatic mode, the operator presses the equipment button, starting the synthesis and, at the end of the operation, issuing a report that allows the process to be followed.

Claims

CLAIMS:

1. GALLIUM-68 MOLECULATION MARKING EQUIPMENT equipped with a portable cabinet (200) provided with an electronic control circuit that acts on the valves (V) and peristaltic pumps (B) by servo motors for the synthesis of the Gallium-68 in a marking circuit (CM) disposed in the internal region of the cabinet (200), characterized by having:

a) a marking circuit (CM) in the form of a flat die (100) provided with niches (110) for the fitting of circuit components (CM) having:

a.1) a Gallium-68 elution generator (G) which receives, by means of a valve (V), a determined volume of hydrochloric acid (HCI) through a pipe (T1) in said elution generator of Gallium-68 (G) occurring the drag of Gallium-68 and Germanium-68 being retained in a chromatographic column (Col);

a.2) a container (C) receiving Gallium-68 eluate from the Gallium-68 elution generator (G) via a pipe (T2) fitted with a valve (V), and a pipe (T3) receives a mixture of ascorbic acid (C ₆ H ₈ 0 ₆ ) and sodium chloride (NaCl) previously adjusted in a valve (V);

a.3) a chromatographic column (Col) interconnected to the container (C) via a pipeline (T4) for the purification of Gallium-68 eluate which returns to the container (C) via a valve-controlled closed loop (V) ;

a.4) a disposal container (Cd) connected to the chromatographic column (Col) through a tubing (T5) for the receiving retained metal contaminants that are routed to a microbiological filter (Fm);

a.5) a molecule marking reactor (R) connected to the container (C) through a pipe (T6) in said container (C) where the Gallium-68 eluate is maintained for about 6 minutes at 125 ° C, said molecule marking reactor (R) which receives, through a pipe (T7), a pre-adjusted mixture of ethanol (E) and sodium chloride (NaCl), and through a pipe (T7a) a peptide (Pep) which mixes with ethanol (E) and sodium chloride (NaCl) following to a pipe (T7b) to be released into reactor (R);

a.6) a phase cartridge (CF) disposed in a pipe (T7c) interconnected to the pipe (T7b) by a valve (V) for the purification of the radiolabeled molecule from reactor (R); a.7) a microbiological filter (Fm) which receives the radiolabeled molecule and forwards it to an end product container (Cpf) positioned in a front niche (11) of the flat die (100);

b) a needle-moving device (300) positioned over the flat die (100) including a base (301) that is vertically movable in vertical guides (302) by compression of springs (303) such that needles (310) disposed in the The ends of the base (301) enter the end product container (Cpf) and the disposal container (Cd) to be withdrawn from the inner region of the cabinet (200).

2. MOLLECLE MARKING EQUIPMENT WITH Gallium-68 according to Claim 1, characterized in that the Gallium-68 elution generator (G) is disposed internally or externally to the cabinet (200).