Method and apparatus for the production of lead 212 for medical use

Abstract

The invention relates to a method for preparing lead (212) for medical use. This method comprises the production of lead (212) by the decay of radium (224) in a generator comprising a solid medium to which the radium (224) is bound, followed by the extraction of the lead (212) from the generator in the form of an aqueous solution A1, characterised in that the lead (212) contained in the aqueous solution A1 is purified from the radiological and chemical impurities, also contained in said aqueous solution, by a liquid chromatography on a column. The invention also relates to an apparatus specially designed for automated implementation in a closed system of said method. It further relates to lead (212) produced by means of this method and this apparatus. Applications: manufacture of radiopharmaceuticals based on lead (212), useful in nuclear medicine for the treatment of cancers, particularly by a-radioimmunotherapy, or for medical imaging, in both humans and animals.

Claims

1. An apparatus for an automated production of lead-212 in a closed system, comprising: a sealed box; a generator comprising a solid medium and radium-224 to produce lead-212 by decay of the radium-224, the radium-224 being bound to the solid medium; and a collector for collecting the purified lead-212; the sealed box comprising: an extractor for extracting the lead-212 from the generator to form an aqueous solution A1; a liquid chromatography column for purifying the lead-212 comprised by the aqueous solution A1 from radiological and chemical impurities; a first connector for connecting the generator with the extractor; a second connector for connecting the extractor with the liquid chromatography column; a third connector for connecting the liquid chromatography column with the collector; and an electronic processor for commanding the extractor, the liquid chromatography column and the first, second and third connectors; the generator and the collector being outside the sealed box, the sealed box comprising an inlet port for allowing the first connector to connect the generator with the extractor, and an outlet port for allowing the third connector to connect the liquid chromatography column with the collector.

2. The apparatus of claim 1, wherein the extractor comprises a circulator for circulating an aqueous solution in the generator.

3. The apparatus of claim 2, wherein the circulator comprises a pump to draw in the aqueous solution and to inject the drawn aqueous solution into the generator.

4. The apparatus of claim 1, wherein the liquid chromatography column comprises a stationary phase which selectively retains the lead-212 from the aqueous solution A1.

5. The apparatus of claim 4, wherein the liquid chromatography column further comprises an eluter for eluting the lead-212 from the stationary phase.

6. The apparatus of claim 5, wherein the eluter for eluting the lead-212 from the stationary phase comprises a circulator for circulating an aqueous solution A3 in the chromatography column.

7. The apparatus of claim 6, wherein the circulator comprises a pump to draw in the aqueous solution A3 and to inject the drawn aqueous solution A3 into the liquid chromatography column.

8. The apparatus of claim 3, wherein the pump is further provided for drawing in an aqueous solution A2 and for injecting the drawn aqueous solution A2 into the liquid chromatography column to wash the stationary phase.

9. The apparatus of claim 6, wherein the collector comprises a flask.

10. The apparatus of claim 9, further comprising a bacteriological purification filter which is placed between the flask and the liquid chromatography column.

11. The apparatus of claim 1, wherein the sealed box further comprises a plurality of inlet ports, each inlet port being provided to be connected to an aqueous solution source, and a fail-safe device to prevent connecting an aqueous solution source to a port with which it is not associated.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 represents the radioactive decay chain of thorium 232.

(2) FIG. 2 is a diagrammatic representation of an example of an embodiment of the apparatus according to the invention.

DETAILED DESCRIPTION OF A SPECIFIC EMBODIMENT

(3) This refers to FIG. 2 which diagrammatically represents an apparatus 20 according to the invention.

(4) As can be seen from this figure, this apparatus firstly comprises a radium 224 generator 22 for the production of lead 212 by radioactive decay of this radium.

(5) This generator consists of a device containing a solid medium, such as a cation exchange resin previously loaded with radium 224, this radium preferably having a radiological purity greater than or equal to 99.5%.

(6) The generator 22 has two ports 24, 26, allowing it to be connected to the other components of the apparatus 20 by ducts (not represented).

(7) This connection allows the lead 212 produced in the generator 22 to be extracted in the form of an aqueous solution.

(8) The apparatus 20 also comprises a chromatography column 28 for purifying, by a liquid chromatography, the lead 212 extracted from the generator 22, from the radiological and chemical impurities which are extracted from this generator jointly with the lead.

(9) This chromatography column can be either a column that has been previously prepared, conditioned and calibrated, or a commercially available ready-to-use column.

(10) In all cases, it contains a stationary phase, such as an extraction chromatography stationary phase, which is capable of retaining lead 212 under certain conditions and also capable of releasing lead 212 by elution under other conditions.

(11) The chromatography column 28 comprises a first port 30 and a second port 32 to connect it to the other components of the apparatus 20.

(12) The apparatus 20 also comprises inlet ports 34 connecting it to the sources 36 of aqueous solutions.

(13) According to a preferred embodiment particularly suited to the use of the apparatus 20 in a nuclear medicine department, each aqueous solution source 36 consists of a syringe filled with a predetermined amount of an appropriate aqueous solution which is to be used during the method. Each syringe 36 is suited to use in nuclear medicine: it has no rubber or silicon grease.

(14) The apparatus 20 also comprises means for pumping 38 the various aqueous solutions contained in the syringes 36, in order to circulate the aqueous solutions in the generator 22 and in the chromatography column 28.

(15) In the embodiment represented in FIG. 2, these pumping means 38 comprise two pumps 40 and 42, a first pump being employed to pump the aqueous solutions used respectively to extract the lead 212 from generator 22 and to wash the stationary phase contained in the chromatography column 28 after it is loaded with the aqueous solution used to extract the lead 212 from the generator 22, whereas the second pump 42 is employed to pump the aqueous solution used to elute the lead 212 from the chromatography column 28.

(16) Preferably, each of the pumps 40 and 42 is of the syringe-pump type in order to pump an exact amount of aqueous solution.

(17) The pumping means 38 also comprise two activators 52 each of which is associated with one of the two pumps 40 and 42 in order to drive this pump. These activators 52 can be electronically controlled to activate pumps 40 and 42 in a relatively precise manner in order to manage the quantity and flow of the pumped aqueous solutions.

(18) The apparatus 20 also comprises outlet ports 44 to collect the aqueous solutions produced by the method according to the invention.

(19) A first port 44 is connected to a flask 46 in which the aqueous solution containing the purified lead 212 is collected. A second port 44 opens into a receptacle 48 in which the other aqueous solutions are collected in order to be disposed of.

(20) A filter 56 having, for example, a pore size of 0.2 μm is placed at the entrance to the flask 46 to complete the chemical purification of lead 212 by a bacteriological purification.

(21) The apparatus 20 also comprises a plurality of multichannel valves 50 as well as a plurality of ducts (not represented) making it possible to selectively connect the components of the apparatus 20 one another for implementation of the method according to the invention.

(22) The valves 50 can be electronically controlled in order to optimise circulation of the aqueous solutions in the apparatus 20.

(23) The apparatus 20 also includes an electronic processor (not represented) for the command and control of the valves 50 and activators 52.

(24) This processor makes it possible to automate the functioning of the apparatus 20, such that the manual operations then consist mainly of connecting certain components of the apparatus 20 prior to implementing the method of the invention and disconnecting these components at the end of the implementation.

(25) The apparatus 20 still comprises a chamber 54 within which the chromatography column 28, the pumps 40 and 42, the activators 52, the valves 50 and, if need be, the electronic processor are placed. This chamber is presented here in the form of a parallelepiped in which the ports corresponding to the inlet ports 34 and outlet ports 44 of the apparatus 20 are found.

(26) The chamber 54 preferably forms a sealed box preventing access to the elements it contains. The chamber also comprises means of access to its interior volume which can be locked. This makes it possible to prevent any non-qualified persons from accessing the components of apparatus 20, particularly the components having some radiological activity, or the components whose functioning can be damaged.

(27) In the embodiment represented in FIG. 2, the radium 224 generator 22 is located outside the chamber 54. The latter therefore has two ports 60 which are crossed by pipes allowing the generator 22 to be connected to the other components of the apparatus 20.

(28) The general dimensions of various components of the apparatus 20 are relatively small, which makes it possible to arrange them in a chamber 54 which is also small in size.

(29) The apparatus 20 can therefore be a portable apparatus that can be used close to the area of usage of lead 212-based radiopharmaceuticals, for example in a nuclear medicine department.

(30) As mentioned previously, the chamber 54 has several inlet ports 34 to which the different sources 36 of aqueous solution are connected to the apparatus. The sources 36 of the aqueous solutions are similar in nature and consist here of predosed syringes.

(31) In order to guarantee the efficacy of the method according to the invention, each aqueous solution source 36 is associated with a single inlet port 34 through which the aqueous solution contained in this aqueous solution source supplies the apparatus.

(32) In order to avoid any reversal between the aqueous solution sources, as a result of connecting a syringe to an inlet port 34 other than the inlet port 34 with which it is associated, the apparatus 20 comprises so-called failsafe means allowing an operator to correctly connect each aqueous solution source 36 to the inlet port 34 with which it is associated.

(33) According to a first embodiment, the failsafe means are of a visual type and consist of colour coding, in other words labelling with a certain colour associated with each inlet port, and each aqueous solution source 36 has the same colour code as the one used to label the associated inlet port 34.

(34) According to another embodiment, the failsafe means are mechanical in nature, in other words each inlet port 34 and the associated aqueous solution source have complementary shapes and sizes and the size and/or shape of an inlet port 34 and of the associated solution source 36 are different from the size and/or shape of another inlet port 34 and the associated solution source 36.

(35) In this way it becomes impossible to connect a solution source 36 to an inlet port 34 with which it is not associated, thus preventing any human error.

(36) According to a preferred embodiment of the apparatus 20, the generator 22 can be disconnected from the rest of the apparatus 20 to be replaced by another similar generator.

(37) In fact, given that radium 224 has a half life of 3.66 days, the generator 22 can only be used for a limited period of time, usually for two weeks, after which the generator no longer contains a sufficient amount of radium 224. It therefore has to be replaced by a new generator.

(38) In a similar manner, the chromatography column 28 can be disconnected from the rest of the apparatus 20 for replacement by another similar column.

(39) The radium 224 generator 22 and the chromatography column 28 are both designed to allow the flow of aqueous solutions without manual intervention.

(40) Thus by simply operating the valves 50 and activators 52 by means of the electronic processor, it is possible to circulate the different aqueous solutions from the syringes 36, in which the solutions are stored, through the generator and/or the chromatography column 28, and to direct these aqueous solutions towards the outlet ports of the apparatus 20, according to controlled flow rates.

(41) The apparatus 20 thus makes it possible to implement the method of the invention in an automated manner.

(42) In addition, the connections are all impermeable, which allows all the aqueous solutions circulating, from the syringes 36 to the flask 46 and to the receptacle 48, in a circuit that is totally isolated from the surrounding environment and, notably, from the ambient air and the pollutants contained therein.

(43) The description which follows refers to an example of implementing the method according to the invention using the apparatus 20 which has just been described.

(44) In this example, the syringes 36 are considered to be filled with an appropriate amount of an aqueous solution and are connected to the apparatus 20 as well as are the flask 46 and the receptacle 48.

(45) Production of the Lead 212

(46) The lead 212 is initially produced in the generator 22.

(47) This production consists in leaving the radium 224 retained on the solid medium contained in the generator 22 to produce lead 212 by radioactive decay, for example over a period of one day.

(48) Extraction of Lead 212

(49) The lead 212 produced in the generator 22 is then extracted from this generator by elution, in other words by circulation in generator 22 of a first aqueous solution which draws out the lead 212 with it.

(50) This extraction consists in taking the first aqueous solution, which is initially contained in a first syringe 36, by the first pump 40 then injecting it into the generator 22, also through this pump.

(51) To do so, the valves 50 are directed by the electronic processor to connect the first pump 40 to the first port 24 of the generator 22.

(52) Loading of the Stationary Phase of the Chromatography Column

(53) The aqueous solution which leaves the generator 22 by the second port 26 of this generator contains lead 212, along with radiological and chemical impurities originating from the solid medium present in the generator 22.

(54) This aqueous solution is taken directly into the chromatography column 28.

(55) To do so, the valves 50 are adjusted to connect the second port 26 of the generator 22 to the first port 30 of the chromatography column 28.

(56) The aqueous solution passes through the chromatography column 28. The lead 212 is retained by the stationary phase contained in this column while some of the radiological and chemical impurities remain in the aqueous solution and therefore leave the column 28 along with the aqueous solution.

(57) Once it has left this column, the aqueous solution is directed towards the receptacle 48.

(58) To do so, the valves are directed by the electronic processor to connect the second port 32 of the chromatography column 28 to the receptacle 48.

(59) Washing of the Stationary Phase of the Chromatography Column

(60) After being loaded, the stationary phase contained in the chromatography column 28 is washed with a second aqueous solution to extract the radiological and chemical impurities it contains from this phase but without extracting the lead 212.

(61) This washing consists in taking the second aqueous solution, which is contained in a second syringe 36, by means of the first pump 40 then injecting it into the chromatography column 28, also through this pump.

(62) The second aqueous solution then passes through the chromatography column 28, drawing with it the radiological and chemical impurities contained in the stationary phase, and is then directed towards the receptacle 48 in which it is collected.

(63) To do this, the valves 50 are directed by the electronic processor to connect the first pump 40 to the first port 30 of the chromatography column 28 and to connect the second port 32 of the chromatography column 28 to the receptacle 48.

(64) Elution of the Lead 212

(65) The lead 212 retained by the stationary phase of the chromatography column 28 is then extracted from this column by elution, in other words by circulation in the chromatography column 28 of a third aqueous solution which draws out the lead 212 with it.

(66) This elution consists in taking the third aqueous solution, which is contained in a third syringe 36, by the second pump 42 then injecting it into the chromatography column 28, also through this pump.

(67) To do this, the valves 50 are directed by the electronic processor to connect the second pump 42 to the first port 30 of the chromatography column 28.

(68) The third aqueous solution therefore passes through the chromatography column 28 drawing out the lead 212 with it.

(69) A volume of aqueous solution leaving the chromatography column 28, which corresponds to the dead volume of the column, is initially directed towards the receptacle 48 in which it is collected.

(70) To do this, the valves 50 are directed by the electronic processor to connect the second port 32 of the chromatography column 28 to the receptacle 48.

(71) Next, the remaining aqueous solution leaving the chromatography column 28 is directed towards the flask 46 where it is collected after having passed through the filter 56.

(72) To do this, the valves 50 are directed by the electronic processor to connect the second port 32 of the chromatography column 28 to the flask 46.

(73) Apparatus Purging

(74) According to a final step, the apparatus 20 is purged by circulating sterile air through it.

(75) This sterile air is obtained by taking ambient air through the first pump 40 then passing this ambient air through a filter 58, having for example a pore size of 0.2 μm, which is placed to the air inlet.

(76) Sterile air is then carried to the receptacle 48 to purge the circuit leading to this receptacle then up to the flask 46 to purge the circuit leading to this flask.

(77) To do this, the valves 50 are directed by the electronic processor to connect the first pump 40 to the receptacle 48 then to the flask 46.

(78) Lead 212 was produced with an apparatus similar to the one that has just been described and using:

(79) a radium 224 generator containing 400 mg of a cation exchange resin (company BIO-RAD—reference AG™ MP50) as the solid medium, this resin having been previously loaded with 10 mL of a solution containing 19 MBq of radium 224 of radiological purity greater than 99.5% (such as that determined by γ spectrometry) as well as 2 moles/L of hydrochloric acid (loading rate: 1 mL/min), then washed with 5 mL of an aqueous solution containing 0.01 mole/L of hydrochloric acid (washing rate: 1 mL/min);

(80) a ready-to-use chromatography column containing 80 mg of “Pb-resin” (company TRISKEM International) as the stationary phase;

(81) 4 mL of an aqueous solution containing 2 mol/L of hydrochloric acid to extract the lead 212 from the generator and to load the stationary phase of the chromatography column (elution and loading rate: 1 mL/min);

(82) 2 mL of an aqueous solution containing 0.5 mole/L of hydrochloric acid to wash the stationary phase of the chromatography column (washing rate: 1 mL/min); and

(83) 1 mL of an aqueous solution containing 0.4 mol/L of ammonium acetate (pH 6.5) to elute the lead 212 from the stationary phase of the chromatography column (elution rate: 0.5 mL/min).

(84) By leaving the radium 224 present in the generator 22 to produce lead 212 for 24 hours, 13 MBq of lead 212 were obtained, presenting:

(85) (1) a radiological purity greater than 99.995%, as established from measurement of the radiological purity presented by this lead 212 after 10 decay periods, this measurement being carried out by means of a germanium detector;

(86) (2) a chemical purity characterised by the presence, in the lead 212 elution solution, of:

(87) less than 11 ppb (parts per billion) of lead (other than lead 212);

(88) less than 2 ppb of vanadium, manganese, cobalt, copper, molybdenum, cadmium, tungsten and mercury;

(89) less than 20 ppb of iron; and

(90) less than 50 ppb of zinc;

(91) (3) bacteriological purity characterised by sterility and less than 0.5 endotoxin unit/mL;

(92) and this in less than 20 minutes between the start of the extraction of lead 212 from the radium 224 generator and the end of the filling of the flask 46 with purified lead 212.

(93) For the purpose of comparison, the radiological purity (established under the same conditions) of the lead 212 produced by a method of the current state of the art ranges from 98 to 99.80%.

REFERENCES CITED

(94) [1] Milanec et al., Cancer Biotherapy and Radiopharmaceuticals 2005, 20 (5), 557-568. [2] Azure et al., World Molecular Imaging Congress, 8-11 Sep. 2010, Kyoto. [3] Horak et al., Journal of Nuclear Medicine 1997, 38, 1944-1950. [4] U.S. Pat. No. 4,663,129.