U.S. patent application number 13/632780 was filed with the patent office on 2013-01-31 for device for synthesis of radiopharmaceutical products.
The applicant listed for this patent is Pierre-Emmanuel Boeyen, Frederic Schmitz, Vincent Tadino. Invention is credited to Pierre-Emmanuel Boeyen, Frederic Schmitz, Vincent Tadino.
Application Number | 20130030168 13/632780 |
Document ID | / |
Family ID | 8175888 |
Filed Date | 2013-01-31 |
United States Patent
Application |
20130030168 |
Kind Code |
A1 |
Schmitz; Frederic ; et
al. |
January 31, 2013 |
Device For Synthesis Of Radiopharmaceutical Products
Abstract
The invention concerns a device for synthesis of
radiopharmaceutical products based on chemical reagents contained
in bottles, said device comprising several reaction compartments,
transfer means between said bottles and said reaction compartments
as well as mechanical means acting on said transfer means and
enabling to monitor and control mechanically the transfer of
chemical reagents. The invention is characterized in that it
comprises: a fixed module including at least the mechanical means;
a removable and disposable module, essentially in the shape of a
support, whereon are arranged the transfer means between said
bottles and said reaction compartments, said removable and
disposable module not including any mechanical means; and means for
securing said removable and disposable module to said fixed
module.
Inventors: |
Schmitz; Frederic; (Fallais,
BE) ; Boeyen; Pierre-Emmanuel; (Corroy-le-Chateau,
BE) ; Tadino; Vincent; (Donceel, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Schmitz; Frederic
Boeyen; Pierre-Emmanuel
Tadino; Vincent |
Fallais
Corroy-le-Chateau
Donceel |
|
BE
BE
BE |
|
|
Family ID: |
8175888 |
Appl. No.: |
13/632780 |
Filed: |
October 1, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10450308 |
Jun 10, 2003 |
8287819 |
|
|
PCT/BE2001/000212 |
Dec 12, 2001 |
|
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13632780 |
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Current U.S.
Class: |
536/124 ;
422/159; 422/501 |
Current CPC
Class: |
A61K 51/1282 20130101;
A61K 51/0491 20130101; A61K 51/04 20130101 |
Class at
Publication: |
536/124 ;
422/501; 422/159 |
International
Class: |
G21C 1/00 20060101
G21C001/00; C08B 37/00 20060101 C08B037/00; B01L 3/00 20060101
B01L003/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 2000 |
EP |
00870323.3 |
Claims
1. A disposable module for use in a device for synthesis of
radiopharmaceutical products from chemical reagents, the disposable
module being essentially in the form of a support plate and
furthermore comprising: means for transferring the chemical
reagents; bottles containing the chemical reagents; the support
plate being provided with positioning means for positioning the
transfer means, and the disposable module wherein the bottles
containing the chemical reagents are pre-metered bottles.
2. The disposable module according to claim 1, wherein the
disposable module does not have any mechanical means.
3. The disposable module according to claim 1, wherein the
positioning means are constituted by grooves in which the transfer
means are placed.
4. The disposable module according to claim 1, wherein the transfer
means are flexible tubes.
5. The disposable module according to claim 1, wherein it
furthermore comprises reaction compartments.
6. The disposable module according to claim 1, wherein the nature
of the support plate and that of the transfer means are such that
they allow washing of the disposable module by steam autoclaving
and/or its sterilisation.
7. The disposable module according to claim 5, wherein the support
plate is made of ABS.
8. The disposable module according to claim 5, wherein the transfer
means are made of silicone.
9. A device for synthesis of radiopharmaceutical products from
chemical reagents contained in bottles, the device comprising a
disposable module according to claim 1 as well as a fixed module
and means of securing the disposable module to the fixed
module.
10. The device according to claim 9, wherein the fixed module
comprises at least mechanical means acting on the transfer means of
the disposable module and enabling to monitor and control
mechanically the transfer of the chemical reagents from the bottles
of the disposable module.
11. The device according to claim 9, wherein the mechanical means
are pistons, the mechanical means, the transfer means and the
positioning means being capable of co-operating so as to form
valves.
12. The device according to claim 9, wherein the securing means
comprise at least one opening, shoulders and fasteners.
13. The device according to claim 12, wherein the shoulders are
located on the support plate, preferably at the four comers of the
support plate, and are capable of fitting into fasteners located on
the fixed module.
14. The device according to claim 12, wherein the opening is
likewise located on the support plate, preferably at the centre of
the plate, and is capable of fitting into a fastener located on the
fixed module.
15. The device according to claim 1, wherein it includes means of
actuating mechanical means of the fixed module.
16. The device according to claim 1, wherein the actuating means
are constituted by an automaton co-operating with a computer and
forming part of the fixed module.
17. A process for synthesising radiopharmaceutical products using
the disposable module according to claim 1 or the device for
synthesis of radiopharmaceutical products from chemical reagents
contained in bottles, the device comprising a disposable module
according to claim 1 as well as a fixed module and means of
securing the disposable module to the fixed module, wherein it
comprises the following stages: at the disposable module, the
transfer means are arranged on the support plate, at the disposable
module, the bottles containing the chemical reagents are fixed to
one of the ends of the transfer means, the disposable module, that
is to say the support plate with the transfer means, is attached to
the fixed module with the aid of securing means, the transfer means
of the disposable module are connected to the various elements of
the fixed module, the various operations required for synthesis of
the pharmaceutical products, including the actuation of the
mechanical means of the fixed module are commanded via an
automaton.
18. The process according to claim 17, wherein before commanding
the various operations required for synthesis of the pharmaceutical
products, a test to verify the tightness of the device is carried
out via the automaton.
19. Use of the disposable module according to claim 1 or of the
device for synthesis of radiopharmaceutical products from chemical
reagents contained in bottles, the device comprising a disposable
module according to claim 1 as well as a fixed module and means of
securing the disposable module to the fixed module for synthesising
radiopharmaceutical compounds containing radio-elements with a
short half-life, preferably .sup.11C, .sup.13N, .sup.15O or
.sup.18F.
Description
SUBJECT MATTER OF THE INVENTION
[0001] The present invention relates to a novel device for
synthesis of radiopharmaceutical products from radioactive
compounds.
[0002] The present invention relates more especially to the use of
this device for synthesis of radiopharmaceutical products from
reagents containing radioactive elements with a short half-life,
such as .sup.11C, .sup.13N, .sup.15O or .sup.18F.
PRIOR ART
[0003] In diagnostic applications, such as Positron Emission
Tomography (PET), use is made of radiochemical compounds, also
called radiopharmaceutical compounds, which are labelled by means
of an element such as .sup.11C, .sup.13N, .sup.15O or .sup.18F. One
example of such compounds is 2-[.sup.18F]fluoro-2-deoxy-D-glucose,
commonly called .sup.18FDG.
[0004] Synthesis of these radiopharmaceutical compounds with a
short half-life is performed in apparatuses that enable the
different chemical compounds for carrying out the synthesis to be
brought into contact and heated during the reaction and allow the
products obtained to be purified.
[0005] To avoid any risk associated with the handling of
radioactive substances, these apparatuses are placed in a shielded
and monitored environment. These apparatuses are generally linked
to an automaton which commands the various operations enabling the
performance of this synthesis, comprising reaction and heating
stages, which are associated with transfers of chemical
reagents.
[0006] Owing to the short half-life of these radioisotopes that are
used, it is necessary to perform this type of synthesis at regular
intervals. This multiplies the risks of contamination from one
synthesis to another, while the end product is intended for
injection into patients.
[0007] Moreover, a certain number of materials contained in the
components of the synthesis apparatus are particularly sensitive to
radioactivity and/or to chemical corrosion. This is the case, for
example, with the valves or tubes allowing transfers to take
place.
[0008] It is therefore necessary to wash and sterilise each
component of the synthesis apparatus at regular intervals,
especially all the tubing and all the valves which allow transfer
of the reagents, hence the need to use components that can be
sterilised easily. Users must furthermore ensure thorough, careful
and regular maintenance of all the components of the apparatus.
[0009] U.S. Pat. No. 5,759,513 discloses an apparatus and a process
for preparing radiochemical compounds in which, with the exception
of the reagent labelled by means of an element with a short
half-life, the reagents required are metered into containers
beforehand. This gives a kit containing the said containers, the
reactors, the columns and the transfer tubes fitted with valves,
which are required for the process. This kit comprises a large
number of elements, including valves. The overall cost does not
allow it to be used as a single-use kit.
[0010] WO-A-93/11871 discloses an apparatus for preparing
radiochemical compounds, comprising a single-use module. This
apparatus is intended to be connected to reagent containers and
comprises means of metering these reagents constituted by injectors
provided with pistons and actuated by stepping motors. Complex,
expensive means that require handling by the operator are necessary
to connect the stepping motors to the rods of the injectors.
[0011] U.S. Pat. No. 5,415,843 describes an apparatus for
manufacturing radiopharmaceutical compounds which has certain
characteristics in common with that described in WO-A-93/11871.
This apparatus includes a single-use disposable kit which comprises
a plate and receptacles but not the connection tubes between the
various receptacles.
[0012] U.S. Pat. No. 5,312,592 also describes an apparatus which
has certain characteristics in common with that described in
WO-A-93/11871. This document relates more especially to a
disposable kit that can be used in the said apparatus and comprises
a plate provided with openings and sleeves to support liquid
injectors and to connect transfer tubes, as well as a hydrolysis
receptacle.
[0013] The article by Chaly T. et al., Appl. Radiat. Isot. Vol.41,
No. 1, pp 29-34 (1990) in Int. J. "Radiat. Appl. Instrum. Part A"
(Pergamon Press) describes a process for producing .sup.18FDG by
using a synthesis unit comprising disposable sterile elements such
as syringes, needles, tubes, adapters and stop valves.
OBJECTS OF THE INVENTION
[0014] It is an object of the present invention to provide a device
for synthesis of radioactive products, in particular
radiopharmaceutical products, from radioactive elements with a
short half-life, which can be used easily.
[0015] In particular, it is an object of the present invention to
provide a device which minimises the risks of contamination from
one synthesis to another.
[0016] It is likewise an object of the present invention to provide
a device which is easier to maintain and service.
[0017] In particular, it is an object of the present invention to
provide a device which can be washed easily and sterilised
easily.
BRIEF DESCRIPTION OF THE INVENTION
[0018] The present invention relates to a device for synthesis of
radiopharmaceutical products from chemical reagents contained in
bottles, the said device comprising several reaction compartments,
transfer means between the said bottles and the said reaction
compartments as well as mechanical means acting on the said
transfer means and enabling to monitor and control mechanically the
transfer of the chemical reagents, characterised in that it
comprises: [0019] a fixed module including at least the mechanical
means, [0020] a removable and disposable module, essentially in the
shape of a support plate, on which the transfer means between the
said bottles and the said reaction compartments are arranged, the
said disposable and removable module not including any mechanical
means, and [0021] means for securing the said removable and
disposable module to the said fixed module.
[0022] The said disposable module preferably furthermore comprises
the said bottles and the said reaction compartments.
[0023] The bottles are preferably pre-metered bottles.
[0024] The support plate preferably comprises means for the precise
positioning of the transfer means.
[0025] The positioning means are preferably constituted by grooves
in which the transfer means are placed.
[0026] The transfer means are preferably flexible tubes, the
mechanical means are pistons, the transfer means, the mechanical
means and the positioning means being capable of co-operating so as
to form valves.
[0027] The securing means preferably comprise at least one opening,
shoulders and fasteners.
[0028] The said shoulders are preferably located on the support
plate, preferably at the four corners of the support plate, and are
capable of fitting into fasteners located on the fixed module.
[0029] The said opening is preferably likewise located on the
support plate, preferably at the centre of the said plate, and is
capable of fitting into a fastener located on the fixed module.
[0030] The nature of the support plate (5) and that of the transfer
means are preferably such that they allow washing of the said
disposable module by steam autoclaving and/or its
sterilisation.
[0031] The support plate is preferably made of ABS and the transfer
means are preferably made of silicone.
[0032] The device preferably includes means of actuating the
mechanical means of the fixed module.
[0033] The actuating means are preferably constituted by an
automaton co-operating with a computer and forming part of the
fixed module.
[0034] The present invention likewise relates to a disposable and
removable module intended for association with a fixed module by
securing means and essentially in the form of a support plate
comprising means for positioning the means for transferring
chemical reagents.
[0035] The said module preferably furthermore comprises bottles and
reaction compartments.
[0036] The said module preferably likewise comprises columns.
[0037] The positioning means are preferably constituted by grooves
capable of receiving transfer means.
[0038] The present invention likewise relates to a process for
synthesising radiopharmaceutical products using the device
according to the present invention and 10 comprising the following
stages: [0039] the transfer means are arranged on the support
plate, [0040] the bottles containing the chemical reagents are
fixed to one of the ends of the transfer tubes, [0041] the said
support plate with the transfer means is attached to the fixed
module with the aid of securing means, [0042] the transfer means
are connected to the various elements of the fixed module, [0043]
the various operations required for synthesis of the pharmaceutical
products, including the actuation of the mechanical means, are
commanded via the automaton.
[0044] Before commanding the various operations required for
synthesis of the pharmaceutical products, a test to verify the
tightness of the device is preferably carried out via the
automaton.
[0045] The present invention also relates to the use of the device
according to the present invention or of the module according to
the present invention for synthesising radiopharmaceutical
compounds containing radio-elements with a short half-life,
preferably .sup.11C, .sup.13 N, .sup.15O or .sup.18F.
BRIEF DESCRIPTION OF THE FIGURES
[0046] FIG. 1 provides a general view of the disposable module
fixed on the fixed module of the device according to the present
invention.
[0047] FIG. 2 represents a perspective view of the fixed module in
the device according to the present invention.
[0048] FIG. 3 represents a perspective view of the front face of
the disposable module without the fixed module in the device
according to the present invention.
[0049] FIG. 4 represents a perspective view of the rear face of the
disposable module without the fixed module in the device according
to the present invention.
[0050] FIG. 5 shows the mechanism for closing the flexible tubes
belonging to the disposable module by means of pistons belonging to
the fixed module according to a preferred embodiment of the
invention.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION
[0051] It should be noted that the figures presented here relate to
a device intended for synthesising .sup.18FDG. These figures are
given purely by way of example to illustrate the invention, but
they do not in any way limit its scope. The person skilled in the
art will easily be able to adapt the various elements of the device
depending on the type of synthesis to be performed.
[0052] As illustrated in FIG. 1, the device according to the
present invention comprises a fixed module 1 and a removable and
disposable single-use module 2. When the device is in operation,
the removable and disposable module 2 is fixed on the fixed module
1.
[0053] FIG. 2 provides a detailed view of the fixed module. The
fixed module 1 is here in the form of a case 7, on which pistons
8a, 8b, 8c, 8e, . . . are arranged.
[0054] The module 1 likewise comprises an automaton controlled by a
computer, although these are not shown here. The automaton controls
all the operations required to implement synthesis of the
radiopharmaceutical products, in particular the movement of the
pistons 8a, 8b, 8c, 8d, 8e,
[0055] Moreover, to enable the device to be used, the module 1
comprises securing means which enable it to be fixed to the
disposable module 2. These securing means can take the form of
fasteners arranged according to a precise configuration. In the
case shown in FIG. 2, these fasteners are of two types. There are,
on the one hand, the four fasteners 12a, 12b, 12c and 12d and the
central fastener 11, the said central fastener 11 here being in the
form of a stud. The presence of the central fastener 11 is intended
for securing the fixing of the module 2 to the module 1. It
furthermore allows the pressure exerted by the pistons 8a, 8b, 8c,
8d, 8e, . . . to be counteracted.
[0056] FIGS. 3 and 4 give a more detailed view of the various
elements of the disposable module according to the present
invention. The disposable module 2 comprises at least: [0057] one
plate 5, in which a network of grooves 6 is formed according to a
precise configuration; [0058] five bottles 3a, 3b, 3c, 3d,3e
containing the pre-metered chemical reagents, respectively
Kryptofix, K.sub.2CO.sub.3, acetonitrile, triflate, water and
sodium hydroxide; [0059] tubes 4a, 4b, 4c, 4d, 4e, . . . for
circulating the chemical products within the synthesis device,
these tubes being flexible in the present case, and one of their
ends being connected to the bottles 3a, 3b, 3c, 3d, 3e,
respectively, [0060] columns, including outlet columns (not shown).
The module 1 here comprises at least four columns, column C.sub.1
as shown in FIG. 3 and columns C.sub.2, C.sub.3, C.sub.4, not
shown, [0061] reaction compartments R.sub.1 and R.sub.2, as shown
in FIG. 1.
[0062] The said plate 5 has a dual function. Its first function is
that the plate 5 serves as a support for the tubes 4a, 4b, 4c, 4d,
4e when these tubes are fixed in the grooves 6. The configuration
of these grooves 6 allows very accurate positioning of the tubes
4a, 4b, 4c, 4d,4e relative to one another. In other words, the
tubes 4a-4e, the pistons 8a-8e and the grooves 6 are capable of
co-operating so as to form valves. The pistons 8a-8e associated
with the portion of the tubes 4a-4e which face them thus form
valves of the "pinch-valve" type, that is to say piston valves.
[0063] It is thus important that the tubes should be positioned
correctly to enable these valves to operate correctly. In
particular, the pistons 8a-8e should be able to act precisely on
the said tubes 4a-4e.
[0064] The second function of the plate 5 is to serve as an
interface between the fixed module 1 and the disposable module 2.
The plate 5 is provided with securing means which enable the said
disposable module 2 to be fixed on the said fixed module 1. By
virtue of their shape, these securing means located on the
disposable module 2 are complementary to the securing means located
on the fixed module 1.
[0065] According to the exemplary embodiment shown in FIGS. 3 and
4, these securing means on the one hand take the form of shoulders
13a, 13b, 13c, 13d, each located at one corner of the plate 5.
These shoulders 13a, 13b, 13c, 13d are capable of fitting into the
respective fasteners 12a, 12b, 12c, 12d. On the other hand, the
securing means take the form of an opening 10 which is located in
the centre of the plate 5 and into which the central fastener 11 of
the fixed module 1 can fit. By virtue of its central position in
the plate 5, the opening 10 makes it possible to ensure that the
disposable module 2 is secured in an optimum manner to the fixed
module 1 while the device is being used.
[0066] However, the securing means can take other forms.
[0067] FIG. 5 illustrates how the pistons 8a-8e located on the
fixed module 1 bring about either the opening or closure of the
tubes 4a-4e of the disposable module 2 as a function of the
movement that they are commanded to make by the automaton. In view
a, this figure shows the head 9 of one of these pistons 8a and a
section of one of the flexible tubes 4a in an open position, that
is to say when the tube 4a is open. In this position, the head 9 of
the piston 8a is disengaged from the tube 4a and transfers of
chemical products are then allowed. When commanded by the
automaton, on the other hand, the head 9 of the piston 8a is
displaced and comes to exert a pressure on the section of the tube
4a, as illustrated in view b, and the tube 4a is then closed,
preventing any transfer of chemical products.
[0068] In relation to the prior-art devices, the present invention
has the original characteristic of being without any mechanical
means, in particular mechanical means of opening and closing the
tubes, these mechanical means being located on the fixed module
1.
[0069] By virtue of this fact, the module 2 can be attached and
removed easily. It can be fixed easily on the fixed module 1. Such
a module 2 likewise has the advantage of being inexpensive, owing
especially to the absence of mechanical means in this module, and,
by virtue of this fact, allows single use.
[0070] According to a preferred embodiment, the plate 5 is made of
ABS and the tubes 4a, 4b, 4c, 4d, 4e, . . . are made of silicone.
The advantage of such a choice in terms of the materials used is
that these elements are capable of withstanding the high pressures,
in particular the pressures exerted by the pistons, during the use
of the device. It likewise makes it possible to limit the waste
resulting from incineration of used disposable modules.
[0071] Insofar as their composition allows, the various elements
constituting this module can be sterilised easily, in particular by
the conventional techniques such as sterilisation by gamma
radiation.
[0072] The example described below is an example of the use of the
device according to the present invention for synthesis of
.sup.18FDG. However, this example is given only by way of
illustration. Other uses are possible.
[0073] To synthesise .sup.18FDG with the device according to the
present invention, .sup.18F.sup.- is first of all extracted from
the mixture H.sub.2.sup.18O--H.sub.2O--.sup.18F.sup.-. To do this,
the mixture is transferred by means of gaseous helium as far as the
column C.sub.1 containing an anion exchange resin, such as QMA
Waters.TM.. Column C.sub.1 allows recovery of the .sup.18F.sup.-,
while H.sub.2.sup.18O--H.sub.2O is transferred to the reaction
compartment R1.
[0074] Tube 4e is opened to allow 0.75 ml of a solution of
K.sub.2CO.sub.3/K2.2.2/H.sub.2O/CH.sub.3CH contained in bottle 3e
to be transferred through column C1 with the aid of a vacuum pump
in a reaction compartment or reactor R.sub.2. The .sup.18F.sup.- is
thus eluted, and it is transferred to reaction compartment
R.sub.2.
[0075] The temperature of the reactor R.sub.2 is increased to
90.degree. C. and H.sub.2O is eliminated by forming an azeotrope
with acetonitrile.
[0076] Tube 4d is then opened, and 0.5 ml of acetonitrile contained
in bottle 3d is then transferred with the aid of a vacuum pump in
reaction compartment R2.
[0077] The traces of H.sub.2O are eliminated by forming an
azeotrope with acetonitrile. The evaporation is continued to
complete the drying.
[0078] Tube 4c is opened so as to transfer with the aid of a vacuum
pump a solution of 13 mg of
1,3,4,6-tetra-O-acetyl-2-O-trifluoromethane-sulphonyl-.beta.-D-mannopyran-
ose in 1 ml of acetonitrile contained in bottle 3c into compartment
R.sub.2. The temperature of the said compartment R.sub.2 is brought
to 85.degree. C.
[0079] The acetonitrile is then evaporated in vacuo while
maintaining the temperature in the reactor R.sub.2 between 90 and
85.degree. C.
[0080] Tube 4b is then opened so as to transfer 1 ml of H.sub.2O
contained in bottle 3b with the aid of a vacuum pump. The reactor
R.sub.2 is then cooled.
[0081] Tube 4a is then opened so as to transfer 1 ml of a solution
of 0.5 N NaOH contained in bottle 3a to reactor R.sub.2 with the
aid of a vacuum pump.
[0082] Nitrogen at a pressure of 400 mbar is used to transfer the
contents of reactor R.sub.2 through purification columns C.sub.2,
C.sub.3, C.sub.4 (not shown) arranged in series at the outlet of
the circuit.
[0083] Tube 4b is opened for a second time to transfer 4 ml of
H.sub.2O from bottle 3b to reactor R.sub.2 with the aid of a vacuum
pump.
[0084] Nitrogen at a pressure of 400 mbar is used a second time to
transfer the contents of reactor R.sub.2 through purification
columns C.sub.2, C.sub.3, C.sub.4.
[0085] Finally, it will be noted that the device according to the
present invention offers the advantage of being particularly
compact, thus reducing the volume of the shielded chamber in which
it is used and hence the quantity of lead.
* * * * *