Patent Application
20150064071
The present invention relates to a disposable module for a device for synthesizing radioisotopes and to a method for manufacturing said module.
Positron emission tomography is a medical imaging technique giving the possibility of viewing the metabolic activity of an organ subsequent to injection of a radioactive tracer, the biological properties of which are known in this organ. One of the most used tracers in nuclear medicine is 18F-fluoro-deoxy-D-glucose abbreviated as [18F]-FDG. This tracer similar to glucose will accumulate in tissues which consume large amounts of sugar like cancer cells, the heart or the brain. The synthesis of [18-F]-FDG is described in the document of Hamacher et al. J. Nucl. Med. 27, 235-238 (1986).
Several automated devices for synthesizing radioactive tracers have been developed. Such a synthesis device is advantageously positioned in a shielding cell.
A device marketed by the applicant under the name of Synthera® is described in document U.S. Pat. No. 7,235,216. This device comprises a fixed module and a disposable module which is positioned on the fixed module.
The fixed module comprises a processor and an interface for the disposable module. The interface of the fixed module is provided with rotary actuators and fluidic connectors leaving the interface and comprises a structure for positioning in an ejectable way a disposable module on said interface so that the rotary actuators and the fluidic connectors may be inserted into the disposable module.
The disposable module comprises:
The processor of the fixed module controls the fluid flow rates as well as the opening and the closing of the valves so as to carry out the different steps for the synthesis reaction of the radiopharmaceutical tracer. Once the radiopharmaceutical product is obtained, the latter is transferred into a container by passing through purification cartridges.
Advantageously, the Synthera® is positioned in a shielding cell comprising a container provided with a hatch located at the front of the fixed module and under the disposable module, so as to be able to collect the disposable module when the latter is ejected at the end of the synthesis.
The Synthera® is relatively compact, and several Synthera® devices may be inserted into a same shielding cell. The Synthera® has the advantage of not requiring any human intervention for removing the disposable module once the synthesis of the radiopharmaceutical tracer has completed. Nevertheless, the disposable module of such a device requires a particular assembly of flexible tubes. These flexible tubes are assembled manually on the plate and the customer has to check that each of the tubes is properly attached. Human errors during the positioning of the tubes are always possible.
Further, the area of the supporting plate is relatively compact (14×5 cm) and comprises locations reserved for flasks of reagents as well as for purification cartridges, leaving not very much room for the positioning of the fluidic connection means for the tubes. Certain tubes may have ends close to each other and may be subject to certain tensile stresses which may cause dislodging of the tube. Certain tubes may also bend upon assembling and cause poor flow of the liquid.
The flasks of reagents are sealed by a septum in rubber and maintained on the supporting plate by attachment means. The supporting plate comprises a movable support on which are positioned metal needles connected to the flexible tubes, each of the needles being positioned under a flask of reagents. Before the synthesis, the movable support is actuated so as to insert the needles into the septum of the flasks of reagents. In order to allow proper insertion of the needles into the flasks, the septa of the flasks have reduced thickness, which may sometimes cause an evaporation of certain volatile solvents. Also, when the movable support is actuated, it happens that flasks are dislodged from their attachment means. Microfluidic devices for the synthesis of radiopharmaceutical products were designed for the purpose of producing very small amounts of radiopharmaceutical products, for applications in scientific research. These devices allow the handling of microliters of solutions concentrated with reagents for productions of radiopharmaceutical products, the activity of which does not exceed 100 mCi. Such a device is described in document WO2007041486. This device is intended to produce small doses of radiopharmaceutical products and comprises a plate of 20×20×4 mm, 25×25×5 mm, 7×7×3 mm or 30×30×6 mm into which are integrated:
This device comprises valves positioned in proximity to the inlets and outlets of the reactor. For producing 18FDG, the reactor is heated to temperatures ranging from 60 to 75°. Overpressures may occur in the reactor during the reaction, due to the small volume of the reactor and to the requirement of closing all the valves for maintaining the liquid in the reactor, which may cause leaks at one or several valves of the reactor. In order to avoid losses of liquids, additional valves or double valves have to be used, which complicates the making of the device.
On the other hand, the reactor is included in the plate; its height is of the order of the diameter of the microfluidic channels and is located in a same plane with the microfluidic channels. The inlets and outlets of the reactor are located on the cylindrical portion of the reactor. The arrangement of the reactor and of the microfluidic channels in the plate as well as the dimensions of the reactor, do not allow good homogenization of the reaction mixture. Several solutions to this problem are proposed in document WO2007041486, nevertheless, the latter complicate the making of the plate. Therefore there is a need for designing a disposable module not having the drawbacks of the aforementioned devices.
Advantageously, such a disposable module has to be able to be inserted on existing fixed modules.
It is also necessary to produce a method for manufacturing disposable modules which is faster and more reliable.
The present invention relates to a disposable module for use in a device for the synthesis of radiopharmaceutical products starting with chemical reagents according to any of the appended claims. In particular, this is a disposable module comprising:
In a preferred embodiment of the module, the interface means appear as (i.e. consist in): an interface plate comprising said at least one valve, said at least one fluid inlet and said at least one outlet of fluids and in contact with said supporting plate, characterized in that at least one of said conduits is integrated into said supporting plate and/or into said interface plate.
Preferably, the totality of said conduits are integrated into the body of the disposable module, or—in the case of the shape according to the previous paragraph—into said supporting plate and/or into said interface plate.
According to an embodiment, the connection between the supporting plate and the interface plate is achieved by side wings secured with the supporting plate, and attached to the interface plate by clips.
The integration of conduits into the supporting plate and/or into the interface plate in particular gives the possibility of avoiding the use of flexible tubes for connecting the flasks, the reactor, the fluid inlets and the fluid outlets with the valves, which considerably reduces the risks of confusion, errors during the mounting of the module, the risk of leaks and of disconnecting the tubes.
Advantageously, said rigid connecting means appear in the form of at least one needle molded with a supporting plate, the flasks to be connected being closed by means of a septum.
According to preferred embodiments of the invention, the disposable module includes at least one, or any suitable combination of the following features:
Another aspect of the invention relates to a method for manufacturing a disposable module for use in a device for the synthesis of radiopharmaceutical products, said method comprising a step for assembling (adhesively bonding) a film, a sheet or a plate onto a substantially planar disposable module plate and provided with grooves, so as to hermetically cover said grooves so as to form conduits or conduit portions able to transfer chemical reagents, gases or products.
Advantageously, the method of the invention comprises the following steps:
Preferably, said hermetically assembling step is carried out by inserting a gasket between said supporting plate and said interface plate.
According to another preferred embodiment of the invention, the method comprises the following steps:
A third aspect of the invention relates to a device for the synthesis of radiopharmaceutical products characterized in that it comprises a disposable module according to the invention. Advantageously, the disposable module of the invention is made by means of the method of the invention.
The figures are not drawn to scale.
The present invention was described in terms of specific embodiments which are illustrative of the invention and which should not be interpreted in a limiting way. More generally, one skilled in the art will appreciate that the present invention is not limited by what has been particularly illustrated and/or described below.
The use of the verbs <<comprise>>, <<include>>, <<consist of>>, <<be provided with>>, or any other alternative, as well as their respective conjugations, does not exclude the presence of elements other than those indicated.
The use of the article <<one>>, <<the>> preceding an element does not exclude the presence of a plurality of such elements.
According to a first aspect, the present invention relates to a disposable module 100 for a macrofluidic device for automated synthesis of a radioactive tracer.
Preferably, the disposable module comprises:
A macrofluidic device for synthesis is defined as a synthesis device for which at least the reactor may contain volumes of liquids greater than 1 ml. Preferably, the flasks of reagents are also able to contain volumes of liquids of more than 1 ml. Still more preferably, the section of the conduits is greater than 1 mm in diameter.
The disposable module 100 is characterized in that at least one conduit is integrated into the body of the disposable module 100. Preferably, the whole of all the conduits is integrated into the body of the disposable module.
The use of flexible pipes as fluid transfer means is thus suppressed.
Preferably, the body of said disposable module 100 is formed with said supporting plate 101 and with a second interface plate 115 perpendicular to said supporting plate 101.
Preferably, said supporting plate 101 is attached against the interface plate 115 by an attachment means.
Preferably, a sealing gasket is comprised between said supporting plate and said interface plate 115.
Preferably, the disposable module 100 comprises:
Preferably, said supporting plate 101 comprises attachment means 107 for said at least one so-called flask.
Preferably, said supporting plate 101 comprises fluidic connection means 114 for the flasks of reagents and fluidic connection means 114′ for the reactor.
Preferably, said at least one flask of reagents is sealed with a rubber septum and said fluid transfer means comprise a pointed fluidic connection means 114 able to pierce through said septum, said fluidic connection means being in a molded plastic material with said supporting plate. The flasks may thus be attached by hand with the required pressure, which gives the possibility of sealing the flasks with thicker septa and avoiding possible evaporations of liquid. With this configuration, the problems of dislodgement of the flasks from their attachment means are also avoided.
Preferably, the supporting plate 101 comprises a tube 108 immersed in said reactor, said plunger tube 108 being connected to said third fluid transfer means in order to discharge the product of the reaction.
Preferably, the plunger tube is molded against the wall of the reactor.
Preferably, a portion of said disposable module 100 is made in polypropylene of medical grade (for example marketed under the name of . . . ) and another portion of said disposable module is made in an ethylene-norbornene copolymer marketed under the name of Topas®. These materials are approved by the FDA (Food and Drug Administration) for producing devices for production of radiopharmaceuticals.
According to a first embodiment of the invention, said reactor 106 is attached on the supporting plate by an attachment means. According to a second embodiment of the invention, the reactor is welded against the body of the supporting plate 101. According to a third embodiment of the invention, a first portion of the reactor is molded with the supporting plate 101 and a second portion of the reactor is welded against the first portion of the reactor. The reactor 106 is preferably made of a plastic material transparent to visible light and chemically inert in the presence of the solutions encountered in the synthesis of radiopharmaceutical products such as for example solutions comprising acetonitrile, acids or bases, and thermoresistant to temperatures above 150° C.
Preferably, the reactor is in ethylene-norbornene copolymer, the glassy transition temperature of which is above 150° C. Such copolymers are marketed by TOPAS Advanced Polymers GmbH, under the names of series 6015 and 6017 having a glassy transition temperature of 160° C. and 178° C. respectively, the glassy transition temperature of the ethylene-norbornene copolymer being proportional to the norbornene level in the copolymer. This material has the advantage of not including any silicon or other metals such as aluminium or boron, which in the state of trace amounts may have an influence on the yield of the nucleophilic substitution reaction as this is described in document WO2011084763.
Preferably, the interface plate 115 of the disposable module 100 comprises an interface 113 (
According to a particular embodiment of the present invention, the body of the disposable module 100 comprises a supporting plate 101 and a second interface plate 115 substantially perpendicular to said supporting plate 101, as illustrated in
The flasks 102, 103, 104 and 105 are preferably sealed with a rubber septum. The first face 109 also comprises fluidic connection means 114, for example needles capable of piercing the septum of said flasks. The first face 109 also comprises first inlet 110 and outlet 110′ fluidic connection means for an F-18 extraction cartridge containing an anion exchanger resin, preferably a QMA Waters cartridge (not shown for the sake of clarity of the drawing), and the second inlet 111 and outlet 111′ fluidic connection means for an 18F-FDG purification cartridge (not shown for the sake of clarity of the drawing). The supporting plate 101 comprises a second face 112, illustrated in
The interface plate 115 comprises a front face 116 supporting said supporting plate 101 and a rear face 113 being used as interface for attaching the disposable module 100 on a fixed module as for example described in document U.S. Pat. No. 7,235,216.
The rear portion 113 of the interface plate 115 comprises:
The disposable module comprises a plurality of channels entirely integrated into the body of the disposable module:
The valves V2, V4, V5 and V6 in this case are three-way valves. All the valves of the disposable module are thus three-way valves, which make the disposable module easier and less costly to manufacture.
Also, the interface plate 115 is changed so that the channels 4 and 5 join up in order to form a common channel 4+5, and so that the channel 9 joins up with channel 8 in order to form a common channel 8+9. With this joining of the inlet channels of reagents it is possible to reduce the number of channels directed towards the reactor 106, which simplifies the supporting plate 101.
According to a second aspect, the present invention relates to a method for manufacturing a disposable module 100 for an automated macrofluidic device for synthesizing a radioactive tracer as described above.
The method comprises a step for assembling (by adhesively bonding or welding for example) a film, a sheet or a plate on a substantially planar disposable module plate and provided with grooves, so as to hermetically cover by means of a film or a plate said grooves in order to form conduits or conduit portions able to transfer chemical reagents, gases or products. According to a first embodiment of the method, the method for manufacturing the disposable module is carried out in the following way:
In a first step, a film, a sheet or a plate 400 is assembled onto a supporting plate 101 comprising:
In a second step, another film, another sheet or another plate 400′ is assembled onto an interface plate 115 comprising:
The film, sheet or plate 400′ assembled on the interface plate 115 is either perforated beforehand or pierced after adhesive bonding so that each of the fluidic connection means is de-obstructed.
Preferably, adhesive bonding of the films, sheet or plate on said supporting plate and on said interface plate is carried out by means of a thermal welding method without any solvents, for example a laser welding method, a heating method with ultrasound or a method using heated blades.
In a third step, the supporting plate 101 is assembled with said interface plate 115, so as to connect said fluidic connection means of said interface plate 115 with said second fluidic connection means of said supporting plate 101.
Preferably, a gasket 401 is inserted between the supporting plate 101 and the interface plate 115 during the assembling step.
Preferably, the interface plate 115 comprises an attachment means 403 in which the supporting plate 101 will be fastened with clips or vice versa. The interface plate 115 also comprises locations for valves positioned on the face 113 opposite to the face 116 provided with grooves.
According to an example of the first embodiment of the method, as illustrated in
In the first step of the method as described above, a film, a sheet or a plate 400 are assembled on each of the opposite faces 109, 112 provided with grooves and with fluidic connections, so as to hermetically cover said grooves.
Preferably, an open cylindrical portion 406 extends perpendicularly downwards from the supporting plate 101 from its lower surface 112. Preferably, a plunger tube 108 is molded against the wall of the open cylindrical portion 406. In a subsequent step to the assembling of the film, sheet or plate 400 on the lower face 112 of the supporting plate 101, a circular part 402 is welded to the base of the cylindrical portion so as to form a reactor 106.
According to a second embodiment of the method illustrated in
In a first step, a first plate 404 comprising:
In a second step, a film, a sheet or a plate 400′ is assembled to an interface plate 115 comprising:
Preferably, the assembling of the films, sheet or plate 400 on said interface plate 115 is carried out by means of a thermal welding method without any solvents, for example a laser method, a heating method with ultrasound or a method using heated blades.
The film, sheet or plate 400 assembled on the interface plate 115 is either perforated beforehand, or pierced after adhesive bonding so that each of the fluidic connection means is de-obstructed.
In a third step, said supporting plate 101 is assembled with the interface plate 115, so as to connect said fluidic connection means of the interface plate 115 with said second fluidic connection means of said supporting plate 101.
Preferably, a gasket 401 is inserted between the supporting plate 101 and the interface plate 115 during the assembling step.
Preferably, the interface plate comprises an attachment means 403 in which will be fastened the supporting plate 101 with clips or vice versa. The interface plate 115 also comprises valves positioned on the face 113 opposite to the face 116 provided with grooves.
Preferably, independently of the embodiment of the method for manufacturing the disposable module, said supporting plate 101 and said interface plate 115 are in ethylene-norbornene copolymer, the glassy transition temperature of which is above 150° C. and said films, sheets or plate covering said grooves are in polypropylene. According to an embodiment, the supporting plate 101 and the interface plate 115 form a single unit part instead of two separate and assembled parts.
According to another embodiment, the module comprises a supporting plate 101 into which are integrated the interface means such as the valves V1-V8, the fluid inlets E1-E2 and the fluid outlets O1-O3. This embodiment may be achieved by increasing the thickness of the supporting plate with respect to the embodiments described above, so as to house the interface means in a wall of said plate which is perpendicular to the plane of the plate. Another possibility is to provide a supporting plate provided with a central portion comprising rigid connection means 114 to at least one flask of chemical reagents, and the portions located laterally with respect to the central portion but in the same plane as the central portion, the lateral portions being provided with said interface means. In the embodiment illustrated in
The supporting plate 101 is assembled from a first plate 502 provided with grooves 503 and a second plate 504 provided with apertures 505 and 506 for connecting to the conduits formed by the grooves 503 after the assembling. The wings 500 are secured with a second plate 504. A first group of apertures 505 are connected to the flasks 506 mounted on the supporting plate. A second group of apertures 507 is connected through the inside of the portion 504 to apertures 508 at the perpendicular face 509 of the second plate 504. Therefore this is an embodiment similar to the one shown in
The interface plate 115 is formed by the assembling of three portions:
| Number | Date | Country | Kind |
|---|---|---|---|
| 2012/0220 | Mar 2012 | BE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2013/056841 | 3/29/2013 | WO | 00 |
