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Title:
METHOD AND DEVICE FOR DISPENSING INDIVIDUAL DOSES OF A RADIOPHARMACEUTICAL SOLUTION
Document Type and Number:
WIPO Patent Application WO/2004/004787
Kind Code:
A2
Abstract:
The present invention relates to a method for dispensing individual doses of a radiopharmaceutical solution, which consists of a radioactive parent solution diluted with a diluting solution. The invention also relates to a computer-generated dose dispenser for dispensing individual doses of a radiopharmaceutical solution at a specified speed. The method and device of the invention are particularly suitable for use in the field of nuclear medicine, and more in particular for use for PET scan applications.

Inventors:
Van Naemen, John (Kastanjestraat 27, Goeferdinge, B-9500, BE)
Monclus, Michel (Rue de la Centenaire 60, Erbaut, B-7050, BE)
Schmitz, Frédéric (Rue François Wathoul 5, Fallais, B-4260, BE)
Goldman, Serge (Avenue de Boetendael 84, Bruxelles, B-1180, BE)
Application Number:
PCT/EP2003/007264
Publication Date:
January 15, 2004
Filing Date:
July 07, 2003
Export Citation:
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Assignee:
UNIVERSITE LIBRE DE BRUXELLES - HOPITAL ERASME (Route de Lennik 808, Bruxelles, B-1070, BE)
Van Naemen, John (Kastanjestraat 27, Goeferdinge, B-9500, BE)
Monclus, Michel (Rue de la Centenaire 60, Erbaut, B-7050, BE)
Schmitz, Frédéric (Rue François Wathoul 5, Fallais, B-4260, BE)
Goldman, Serge (Avenue de Boetendael 84, Bruxelles, B-1180, BE)
International Classes:
A61K51/12; G21F5/015; (IPC1-7): A61K51/00; G21F5/015
Attorney, Agent or Firm:
Brants, Johan Philippe Emile (De Clercq, Brants & Partners Edgard Gevaertdreef 10a, Sint-Martens-Latem, B-9830, BE)
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Claims:
CLAIMS
1. A method for dispensing individual doses of a radiopharmaceutical solution, said radiopharmaceutical solution consisting of a radioactive parent solution diluted with a diluting solution, in which a parent solution is provided having a volume V1 and a radioactivity R at time T, said radioactivity undergoing a decay; a diluting solution is provided, having a volume V2 and no radioactivity; an individual dose of a radiopharmaceutical solution is requested having a volume V'and a radioactivity R'at time T' ; a volume AV1, being a portion of the volume V1 of said parent solution, and a volume AV2, being a portion of the volume V2 of said diluting solution, are calculated for obtaining said requested radiopharmaceutical solution having a volume V', being AV1 + AV2, and a radioactivity R'at time T' ; and said AV1 and AV2 volumes are dispensed in individual doses.
2. A method according to claim 1, wherein said parent solution is homogenized prior to taking the volume AV1 of the volume V1 of said parent solution.
3. A method according to claims 1 or 2, wherein the volume AV2, being a portion of the volume V2 of said diluting solution, is zero.
4. A method according to any of claims 1 to 3, wherein said AV1 and AV2 volumes are dispensed into one or more syringes and/or vials.
5. A method according to claim 4, wherein said AV1 and AV2 volumes are dispensed into one or more syringes and/or vials at a specified speed.
6. A method according to any of claims 1 to 3, wherein said AV1 and AV2 volumes are dispensed into a patient.
7. A method according to claim 6, wherein said #V1 and #V2 volumes are dispensed into a patient at a specified speed.
8. A method according to any of claims 1 to 7 wherein individual doses of the said radiopharmaceutical solution are dispensed through a single use system.
9. A method according to any of claims 1 to 8, wherein the volume AV1 is taken from the volume V1 of the parent solution through a single entry in said parent solution, said entry being a needle remaining in the parent solution during the complete operation.
10. A computer program wherein the calculations of the method according to any of claims 1 to 9 are performed.
11. Computer adapted and programmed to carry out the computer program according to claim 10.
12. Use of the method according to any of claim 1 to 9 for providing an individual dose for positron emission tomography (PET) scan application.
13. A device for dispensing individual doses of a radiopharmaceutical solution, said radiopharmaceutical solution consisting of a radioactive parent solution diluted with a diluting solution; said device comprising a first container for containing a parent solution; a second container for containing a diluting solution; a reservoir for receiving said parent solution and said diluting solution; a tubing system for conducting said parent solution and said diluting solution to said reservoir comprising a first tube provided with a first pumping device and connected to said first container, a second tube provided with a second pumping device and connected to said second container and a third tube connected to said first and said second tube; a fitting for connecting said tubes of the tubing system; and control units for controlling said pumping devices; and characterized in that said first container is provided with a means for enhancing the homogeneity of said parent solution.
14. A device according to claim 13, wherein said means for enhancing the homogeneity of said parent solution comprises a moving plate.
15. A device according to claim 13 or 14, wherein said pumping devices comprise peristaltic pumps.
16. A device according to any of claims 13 to 15, comprising tubing guides for guiding the first and the second tube, said tubing guides being attached to said pumping devices.
17. A device according to any of claims 13 to 16, whereby said device is provided within a shielding cabinet suitable for limiting the emission of ionizing radiation.
18. A device according to any of claims 13 to 17, further comprising valves for priming.
19. A device according to any of claims 13 to 18, wherein the first tube is provided with a male luer lock, said male luer lock being protected with a stopcock.
20. A device according to any of claims 13 to 19, wherein the second tube is provided with a female luer lock, said female luer lock being protected with a stopcock.
21. A device according to any of claims 13 to 20, wherein the third tube is provided with a female luer lock, said female luer lock being protected with a stopcock.
22. A device according to any of claims 13 to 21, whereby said diluting solution comprises a physiological saline solution.
23. A device according to any of claims 13 to 22, whereby said reservoir for receiving the individual doses of radiopharmaceutical solution comprises one or more syringes and/or vials or a combination thereof.
24. A device according to any of claims 13 to 22, whereby said reservoir for receiving the individual doses of radiopharmaceutical solution comprises a needle, said needle being applied to a patient.
25. A computergenerated method for dispensing individual doses of a PET scan radiopharmaceutical solution whereby said PET scan radiopharmaceutical solution is automatically generated from a parent solution such that the said PET scan radiopharmaceutical solution has a requested volume V'with a radioactivity R'at a time point T'.
Description:
METHOD FOR DISPENSING INDIVIDUAL DOSES OF A RADIOPHARMACEUTICAL SOLUTION FIELD OF THE INVENTION In a first aspect the present invention relates to a method for dispensing individual doses of a radiopharmaceutical solution. In a second aspect the invention concerns a computer program suitable for processing the method of the invention. In a third aspect, the present invention relates to the use of the method according to the invention for PET-scan applications. In a fourth aspect the invention relates to a device for dispensing individual doses of a radiopharmaceutical solution.

BACKGROUND OF THE INVENTION Radioisotopes, compounds containing radioactive forms of atoms, are today employed in an increasing range of processes in the field of food preparation, agriculture, water supply, biological and industrial research. One of the most important uses of these elements is in the field of medicine, where radioisotopes of elements have become an important tool in diagnoses using nuclear imaging. Diagnostic radioisotopes are used as markers within the body. They may be used in the free form, allowing the body's handling of the elements to be traced, but more often they are attached to selected molecules as a label allowing the passage and distribution of these molecules to be traced in the body.

PET scan, also called positron emission tomography, is an imaging technique that uses radioisotopes, which emit positrons. This technique provides computerized images of the metabolic activity of body tissues, which may be used for the purpose of imaging, evaluating organ function, or localizing diseases or tumors in the body. Radioisotopes are introduced into the body. The choice of radioisotopes depends on what is being scanned.

Generally, a radioisotope is chosen that will accumulate in the area of interest, or that will be selectively taken up by certain types of cells, f. e. cancer cells. The introduced radioisotopes will induce radiation consisting of gamma rays, which is detected using special detector cameras, placed around the area of interest for a period of time. Once enough gamma rays are detected, an image can be computer-generated representing where the isotope localized within the organ or body.

The dangers of ionising radiation are well known and apply to all persons coming into contact with radiation. Especially the staff involved in the preparation of radio- pharmaceutical solutions, i. e. solutions containing molecules labeled with a radioisotope,

are exposed to an additional risk posed by the selectivity of the radio-labels. The need to minimize the exposure of the employees to radiation, coupled with the problems associated with the manipulation of radiopharmaceutical solutions under aseptical conditions, has favored the adoption of automated systems to dispense doses of radiopharmaceutical solutions.

Different commercially available systems exist to distribute the doses of radiopharmaceutical solutions. For example, US 5,039, 863 describes an automatic radioisotope filling apparatus equipped with a radioisotope vial containing a radioisotope solution, a saline vial containing a physiological saline solution, a dilution vial to which a predetermined amount of the radioisotope solution and a predetermined amount of the physiological saline solution are to be transferred to prepare a diluted radioisotope solution, a radiation detector for measuring the radioactive intensity of the diluted radioisotope solution prepared in the dilution vial, and a plurality of label vials containing a drug to be labeled.

However, in these systems several problems currently exist. One problem is that the described systems are relatively complex. Another problem comprises the inaccurate determination of the radioactivity of the doses of radiopharmaceutical solutions at defined time points. While commercially available systems allow the dispensing of well-determined volumes of radiopharmaceutical solutions, these systems do not enable to provide determined accurate volumes of radiopharmaceutical solutions having a defined accurate radioactivity at a particular time point. The use of inadequate amounts of radioactivity in the doses of radiopharmaceutical solutions implies increased risks and dangers. Not only patients receiving the radiopharmaceutical solutions, but also the employees involved in the administration of the radiopharmaceutical solutions to the patients, may be exposed to radioactivity levels which are superior to the actually requested levels.

Therefore, it is an object of the invention to provide a method for dispensing doses of a radiopharmaceutical solution being well-determined in terms of volume and radioactivity at a particular time point. The invention aims to provide a method enabling to dispense well- defined volumes of a radiopharmaceutical solution having a precisely determined radioactivity at a particular time point. Another object of the invention consists of providing a better dosage of the radioactivity required for preparing the radiopharmaceutical solutions in order to reduce the preparation costs. Importantly, it is also an object of the

present invention to greatly reduce the risks and dangers related to the preparation and use of radiopharmaceutical solutions.

SUMMARY OF THE INVENTION In a first aspect, the present invention relates to a method for dispensing individual doses of a radiopharmaceutical solution, said radiopharmaceutical solution consisting of a radioactive parent solution diluted with a diluting solution, in which - a parent solution is provided having a volume V1 and a radioactivity R at time T, said radioactivity undergoing a decay; - a diluting solution is provided, having a volume V2 and no radioactivity; - an individual dose of a radiopharmaceutical solution is requested having a volume V'and a radioactivity R'at time T' ; - a volume EV1, being a portion of the volume V1 of said parent solution, and a volume AV2, being a portion of the volume V2 of said diluting solution, are calculated for obtaining said requested radiopharmaceutical solution having a volume V', being AV1 + AV2, and a radioactivity R'at time T' ; and - said AV1 and AV2 volumes are dispensed in individual doses.

The method of the invention enables to dispense doses of a radiopharmaceutical solution being well-determined in terms of volume V', and radioactivity R'at a particular time point T', which is a feature essentially important for radiopharmaceutical solutions having a small half-life values. The invention provides a method for improved dosage of the radioactivity required for preparing the radiopharmaceutical solutions. As a consequence, the use of excessive amounts of radioactivity is avoided, which is not only cost-effective but also very advantageous with regard to reducing risk of exposure of patients and employees to radioactive substances.

The method permits to prepare and deliver individual doses of radiopharmaceutical solutions having a well-defined volume and a well-defined level of radioactivity at a requested time-point. In addition, the present method enables to prepare a series of individual doses of radiopharmaceutical solutions, which all have a (same) well-defined volume and a (same) well-defined level of radioactivity at a requested time-point.

According to the present invention, it is possible to prepare exactly defined doses of radiopharmaceutical solutions having exactly defined levels of radioactivity by

a) calculating and dispensing the exact volume of required parent solution and the exact volume of required diluting solution which need to be mixed in order to obtain a desired radiopharmaceutical solution and b) homogenizing the parent solution before taking a volume of the parent solution to mix it with a volume of the diluting solution.

According to a particular aspect of the present invention, the parent solution is thus homogenized prior to taking a volume AV1 of the volume V1 for preparing the radiopharmaceutical solution having a volume V'and radioactivity R'at a particular time point T'. Homogenization of the parent solution may be done continuously or discontinuously. Preferably, the parent solution is continuously homogenized and not only homogenized before dispensing the required volume AV1 and mixing it with a volume of dilution solution. Homogenization also permits to minimize differences between radiopharmaceutical solutions that are prepared in order to all have a (same) well-defined volume and a (same) well-defined level of radioactivity at a requested time-point.

In second aspect the invention relates to a device for dispensing individual doses of a radiopharmaceutical solution, said radiopharmaceutical solution consisting of a radioactive parent solution optionally diluted with a diluting solution; said device comprising a first container for containing a parent solution; a second container for containing a diluting solution; a first tube connected to said first container for conducting said parent solution, said first tube being provided with a first pumping device; a second tube connected to said second container for conducting said diluting solution, said second tube being provided with a second pumping device; control units for controlling said pumping devices; a third tube being connected to said first and said second tube for conducting said parent solution and said diluting solution to a reservoir; and a reservoir for receiving said parent solution and said diluting solution; characterized in that said first container is provided with a means for enhancing the homogeneity of said parent solution.

The method and device of the invention are particularly suitable for use in the field of nuclear medicine, and more in particular for use for PET scan applications.

DETAILED DESCRIPTION OF THE FIGURES The invention is adequately depicted in the accompanying drawings. Figure 1 describes an arrangement of the parent solution 4, the diluting solution 2 and the reservoir 28 receiving the final dose of a radiopharmaceutical solution. Figure 2 describes the tubing system used to dispense the parent solution and the diluting solution into doses, comprising three tubes, which are interconnected with a fitting 20. Figure 3 describes the fitting of a first and a second tube into two tubing guides 8. Figure 4 describes the fitting of the two tubing guides 8 onto the peristaltic pumps 3. Figure 5,6, 7,8 and 9 describe alternative arrangements of the device according to the invention.

DETAILED DESCRIPTION OF THE INVENTION A radiopharmaceutic is a molecule labeled with a radioisotope. The radiopharmaceutic is usually solvate in a bulk homogeneous injectable solution. Depending on the half-life of the radioisotopes, a volumic amount of the bulk homogeneous solution has to be taken more or less frequently to prepare the final dose ready for injection.

The volumic radioactivity (Ci/ml) changes constantly with time because of the decay of the radioisotopes. Therefore, in order to keep a fixed amount of radioactivity, different volumes will be taken from the bulk solution. For instance, a bulk solution of ['8F] FDG containing 1.4 Ci at time t=0 hour in a volume of 70 mi can be used to prepare a dose ready for the final injection of 3 mCi. This dose will be supplied in different volumes taking into account the half-life of the radioisotopes. At time t=0 hour, a final dose of 3 mCi is contained in a volume of 0.15 ml. At time t=109,8 minutes, a final dose of 3 mCi is contained in a volume of 0.3 ml. At time t=960 minutes, a final dose of 3 mCi is contained in a volume of 62 mi.

Another point to be highlighted is the reasonable volumic amount that can be used for final injection whatever is the amount of radioactivity. A limit of 20 ml injected solution is a value generally accepted. On the other hand the injection of very small amount of volume (< 1 ml) is not realistic. For example, detailed distribution of doses of 10 mCi or 5 mCi from a 100 ml bulk homogeneous solution of 100 mCi of radiopharmaceutics labeled with a radioisotope of 109,8 minutes half-life is described in table 1 and table 2.

Table 1 A Time Time AO decay time Volumic activity Delivered Volume (hours) (hours) (mCi) (mCi/ml) activity (mCi) (ml) 0 7 1000 1 10 10 1 8 685 0. 685 10 14. 6 2 9 469 0. 469 10 21. 3** 3 10 321 0. 321 10 31.1** 4 11 220 0. 220 10 45. 5** 5 12 150 0. 150 10 66. 5** 6 13 103 0. 103 10 97.1** 7 14 71 0. 071 10 **** 8 15 48 0. 048 10 **** 9 16 33 0. 033 10 **** 10 17 23 0. 023 10 **** 11 18 1. 6 0. 01610**** ** the volume of radioactive solution to be taken to deliver the accurate amount of radioactivity is higher than 20 ml **** the volume of radioactive solution to be taken to deliver the accurate amount of radioactivity is higher than the volume of the starting solution Table 2 A Time Time AO decay time Volumic activity Delivered Volume (hours) (hours) (mCi) (mCi/ml) activity (mCi) (ml) 0 7 100 1 5 5 1 8 68.5 0. 685 5 7. 3 2 9 46.9 0. 469 5 10. 7 3 10 32.1 0. 321 5 15. 6 4 11 22.0 0. 220 5 22. 7** 5 12 15.0 0. 150 5 33.2** 6 13 10.3 0. 103 5 48. 5 7 14 7.1 0. 071 5 70.9** 8 15 4.8 0. 048 5 **** 9 16 3.3 0. 033 **** 10 17 2.3 0. 023 5 **** 11 18 1.6 0.016 5 **the volume of radioactive solution to be taken to deliver the accurate amount of radioactivity is higher than 20 ml **** the volume of radioactive solution to be taken to deliver the accurate amount of radioactivity is higher than the volume of the starting solution Detailed distribution of doses of 3 mCi from a 100 ml bulk homogeneous solution of 1000 mCi of radiopharmaceutics labeled with a radioisotope of 109,8 minutes half-life is described in table 3.

Table 3

A Time Time AO decay time Volumic Delivered activity Volume (hours) (hours) (mCi) activity (mCi) (mi) mCi/ml 0 7 100 10 3 0. 33 ** 1 8 68. 5 6, 85 3 0. 44 ** 2 9 46. 9 4, 69 3 0. 64 ** 3 10 32. 1 3, 21 3 0. 93 ** 4 11 22. 0 2, 20 3 1. 36 5 12 15. 0 1, 50 3 2 6 13 10. 3 1, 03 3 2.91 7 14 7. 1 0. 71 3 4.22 8 15 4. 8 0. 48 3 6.25 9 16 3. 3 0. 33 3 9.09 10 17 2. 3 0. 23 3 13.04 11 18 1.6 0.16 3 18.75 ** the volume of radioactive solution to be taken to deliver the accurate amount of radioactivity is lower than 1 ml Thus, when calculating a desired radioactivity and volume for a radiopharmaceutical solution at a particular time point, two important aspects need to be considered. The volumic radioactivity (Ci/ml) of the bulk solution used to prepare the radiopharmaceutical solution changes constantly with time because of the decay of the radioisotopes.

Therefore, in order to obtain a desired radioactivity and volume for a radiopharmaceutical solution at a particular time point, different volumes will have to be taken from the bulk solution. In addition, the reasonable volumic amount that can be used for final injection in a patient is restricted, whatever is the amount of radioactivity. A limit of 20 ml injected solution is a value generally accepted. On the other hand the injection of very small amount of volume (< 1 ml) is not realistic. The present invention takes both aspect into account and provides an innovative method enabling to dispense individual doses of a radiopharmaceutical solution, whereby the volume and the radioactivity of the dispensed doses are defined at a particular time point.

In a first embodiment, the invention relates to a method for dispensing individual doses of a radiopharmaceutical solution, said radiopharmaceutical solution consisting of a radioactive parent solution diluted with a diluting solution, in which - a parent solution is provided having a volume V1 and a radioactivity R at time T, said radioactivity undergoing a decay; - a diluting solution is provided, having a volume V2 and no radioactivity;

-an individual dose of a radiopharmaceutical solution is requested having a volume V'and a radioactivity R'at time T' ; a volume AV1, being a portion of the volume V1 of said parent solution, and a volume AV2, being a portion of the volume V2 of said diluting solution, are calculated for obtaining said requested radiopharmaceutical solution having a volume V', being AV1 + AV2, and a radioactivity R'at time T' ; and said AV1 and AV2 volumes are dispensed in individual doses.

According to the method of the invention, a"radiopharmaceutical solution"is prepared using a parent solution and a diluting solution. A"parent solution"is defined as a solution containing radio labeled molecules and having a particular radioactivity R at a particular time point T, whereby the radioisotopes undergo a decay. The term"a bulk homogeneous solution"or"a bulk solution"are used herein as synonyms for a parent solution. A"diluting solution"refers to a solution, which does not contain any radioisotopes and consequently does not have any radioactivity level. This solution may f. e. consist of a physiological saline solution.

The diluting solution is added to the parent solution in order to obtain a radiopharmaceutical solution having a well-defined volume and radioactivity at a particular time point. The method involves the calculation of the required volume of diluting solution and parent solution that are to be combined in order to obtain the requested radiopharmaceutical solution. Thus, practically a portion (AV2) of the volume V2 of the diluting solution will be combined with a portion (AV1) of the volume V1 of the parent solution. However, as it should be understand from the present invention, the addition of the diluting solution to the parent solution is not always necessary. In a particular case, a requested volume of radiopharmaceutical solution having a well-defined radioactivity at a particular time point may essentially consists of the parent solution without need for diluting the parent solution with a diluting solution. Therefore, in another embodiment, the invention relates to a method wherein the volume AV2, being a portion of the volume V2 of the diluting solution, is zero. Practically, the method according to the invention involves the following steps. A parent solution is prepared having a radioactivity value Ro, and a volume V1, at a particular time point, To. As the radioactivity value of the parent solution changes constantly with time due to the decay of the radioisotopes, its radioactive value will be different at the time it is used for preparing the radiopharmaceutical solution.

Therefore, prior to starting the preparation of a radiopharmaceutical solution, i. e. at a time- point T, the radioactivity value of the parent solution comprises R. The radioactive value of

the parent solution may be measured at that time point T, i. e. when starting the preparation of the radiopharmaceutical solution preparation, by using a calibrator.

Alternatively, as the decay of radioisotopes is a well-known and well-established process, starting from the parent solution having a radioactivity value Ro at time To ; the radioactivity level R of the parent solution at the time T can also be determined using computer programs.

According to the invention, the operator may want to prepare a volume V'of a radiopharmaceutical solution having a radioactive value of R'at time-point T'. The method of the invention automatically determines the required volume of parent solution AV1 and of diluting solution AV2 needed for preparing the radiopharmaceutical solution having these particular conditions.

The parent solution is diluted with a suitable amount of diluting solution according to the calculated need. The AV1 parent volume and the AV2 diluting volume form together the requested radiopharmaceutical solution having a volume V'. The prepared radiopharmaceutical solution is subsequently aseptically filled into recipients.

The method of the invention will precisely calculate the volume of parent solution and diluting solution, which is necessary to obtain a specific volume of a radiopharmaceutical solution having a well-determined radioactivity level at a specific time-point. The volume of the parent solution corresponding to a desired radioactivity of the radiopharmaceutical solution at a specific time point varies, depending upon the initial level of radioactivity and the half-life of the radioisotopes in the parent solution. When the parent solution is highly radioactive only a few milliliters of this solution may be required to produce a suitable radiopharmaceutical solution. Conversely, a radiopharmaceutical solution prepared from a parent solution that has a low level of radioactivity may require the use of a large amount of the parent solution.

Advantageously, the present invention provides a process that allows the dispensing of the radiopharmaceutical solution during the whole time the parent solution can be used. It implies distribution of very low volumes (< 150 ut) to very large volumes (the entire bulk parent solution) of parent solution.

The method provides a completely automated system that allows to obtain a radiopharmaceutical solution precisely calibrated in terms of radioactivity, volume at a particular time point without any manual interference. Also, the need for measuring the radioactivity level of the radiopharmaceutical solution is restricted. Only a single

measurement of the radioactivity level of the parent solution prior to use in the preparation of the radiopharmaceutical solution may be necessary. Alternatively, the radioactivity level of the parent solution required at that moment may be calculated based on a single measurement of the radioactivity level of an aliquot of the parent solution. The radioactivity level of the parent solution is permanently updated in function of the radioactivity decay and withdrawals using computer program. Further, handling of the radioactive solutions is restricted to a minimum. Consequently, exposure to the radioactive solutions and the risks and dangers related thereto are reduced for the staff involved in the preparation of radiopharmaceutical solutions. Thus, the method guarantees the maximal precision of the dose to inject into the patient and the protection of the operator.

Another advantage of the method of the invention relates to the precise adjustment of the distributed volume to a final suitable volume. Especially very low volumes (< 1 ml) are not easily handled and injected. The method allows to adjust the injectable solution to a useful volumic amount (> 1 ml). The error on the distributed volume is lower than 5 % whatever is the volume requested for the doses. Also, because radiopharmaceutical solutions can be prepared having a precisely determined volume and radioactivity at a particular time- point, radiopharmaceutical solutions may be prepared in advance and stored.

In another embodiment, the invention relates to a method wherein the parent solution is homogenized prior to taking the volume AV1 of the volume V1 of said parent solution. Due to the very low concentration of some prepared radiopharmaceutical solutions, the bulk parent solution has to be homogenized before dispensing. The homogenization can be done with a moving plate onto which the vial containing the bulk solution is placed but also with stirring bars, bubbling gas,... In a preferred embodiment, the homogenization of the parent solution is done using a moving plate.

In another embodiment the method of the invention comprises distributing the obtained radiopharmaceutical solution into a syringe and/or a vial. In particular the distribution of the radiopharmaceutical solution takes place at a specified speed of injection. In another embodiment, the radiopharmaceutical solution obtained is dispensed into a patient. Also in this case, the distribution of the radiopharmaceutical solution takes place at a specified speed of injection. According to the invention, the doses of obtained radiopharmaceutical solution can be distributed in any type of syringes and in any type of vials or passed through a 0. 22 um sterilizing filter under aseptical conditions. The method enables the

distribution of doses into syringes and vials. Most of the commercially available systems only distribute doses into syringes or vials but not in syringes and vials.

In a further embodiment the invention relates to a method wherein individual doses of the said radiopharmaceutical solution are dispensed through a single use system. The single use system is composed of a tubing, fitting, a saline solution, valves and needles (see also Figures 1,2, 3,4, 5,6, 7,8, 9). All the components of the single use system are already sterile or can be sterilized. The single use system has to be replaced each time the parent solution is renewed. This feature provides several important advantages. The radiopharmaceutical solution is obtained free from any cross contamination coming from earlier preparation of radiopharmaceutical solutions. Moreover, the method of the invention only accepts a one-way flow for the dispensed solution. There is no possibility to bring back any amount of the dispensed dose into the bulk parent solution.

Importantly, in a preferred embodiment of the method of the invention, a volume AV1 is taken from the volume V1 of the parent solution through a single entry in said parent solution, said entry being a needle remaining in the parent solution during the complete operation. In other known systems, several entries are made to dispense the parent solution out of its container. In contrast, the present invention provides a single entry made in the container containing the parent solution. This entry may consist of a single needle poured in the parent solution, which will not be removed out of the parent solution during the course of the dispensing operation. This feature enables to avoid any contamination of the parent solution.

In another embodiment the invention relates to a method whereby the single use system is adjusted into a mechanical system. The single use system can act only after adjustment into mechanical systems, which may for instance comprise peristaltic pumps (see also figure 2, 3, 4).

In a further embodiment, the invention provides a computer program wherein the calculations of the method of the invention are performed. The computer program according to the invention calculates the preparation, calibration, dilution and the dispensing of individual patient preparations, procedures which are currently carried out manually. The software program which controls the method steps of the invention comprises proven security and safety principles including authorised operator control, authorized manual intervention, database recording of radioactive materials, record of

patient data and doses, permanent record of radioactive source, calibration and campaigns, fault display. The invention also relates to a computer adapted and programmed to carry out the computer program according to the invention.

The invention is particularly suitable for applications in the field of nuclear medicine, where individual and well-established dosages or aliquots of a short-lived radioactive solution are required. In general, the use of radiopharmaceutical solution in nuclear medicine may have diagnostic or therapeutic purposes. Therapeutic radioisotopes contained within radiopharmaceutical solutions can be directed to malignant tumors to deliver radiation directly to cancerous cells, as in radium therapy for breast cancer. They can also be attached to biologically active molecules to seek out tumor cells in particular body tissues.

Diagnostic radioisotopes contained within radiopharmaceutical solutions are used as markers within the body. They may be used in the free form, allowing the body's handling of the elements to be traced, but more often they are attached to selected molecules as a 'label'or'tracer'allowing the passage and distribution of these molecules to be traced in the body.

A particular example of diagnostic technique wherein radioisotopes, and radiopharmaceutical solutions, are used consists of the PET scan technique. Situations wherein a PET scan can help diagnosis include but are not limited to brain injuries or diseases; cardiovascular diseases; early brain changes/diseases; tumors or anatomical abnormalities ; the cause of mental disorders or areas affected by a clot or stroke. During the PET scan technique, a small amount of a radiopharmaceutical solution will be injected into one of the patient's veins. In a preferred embodiment, the method of the invention is used for providing an individual dose of a radiopharmaceutical solution for PET scan application. However, it is clear that the application of the method of the invention may not be limited to the field of nuclear medicine and the application of the radiopharmaceutical solutions may be extended beyond the field of nuclear medicine.

In another embodiment, the invention relates to a computer-generated method for dispensing individual doses of a PET scan radiopharmaceutical solution whereby said PET scan radiopharmaceutical solution is automatically generated from a parent solution such that the said PET scan radiopharmaceutical solution has a requested volume V'with a radioactivity R'at a time point T'. As it should be understand from this embodiment, the PET scan radiopharmaceutical solution is automatically generated, i. e. without need for manual interference by an employee, using a computer-controlled method. The method

consists of preparing individual doses of a PET scan radiopharmaceutical solution having a specifically requested volume V'with a radioactivity R'at a time point T'starting from a radioactive parent solution. The parent solution may be diluted with one or more diluting solutions, in order to provide individual doses of the PET scan radiopharmaceutical solution which have the volume V'with a radioactivity R'at a time point T'as it is requested.

The invention also provides for a computer-generated dose dispenser. In another embodiment, the invention relates to a device for dispensing individual doses of a radiopharmaceutical solution, said radiopharmaceutical solution consisting of a radioactive parent solution diluted with a diluting solution ; said device comprising - a first container for containing a parent solution; - a second container for containing a diluting solution; - a reservoir for receiving said parent solution and said diluting solution; - a tubing system for conducting said parent solution and said diluting solution to said reservoir comprising a first tube provided with a first pumping device and connected to said first container, a second tube provided with a second pumping device and connected to said second container and a third tube connected to said first and said second tube; - a fitting for connecting said tubes of the tubing system; and - control units for controlling said pumping devices; and characterized in that said first container is provided with a means for enhancing the homogeneity of said parent solution.

The said means for enhancing the homogeneity of said parent solution can include a moving plate onto which the vial containing the bulk parent solution is placed but also stirring bars, bubbling gas,... In a preferred embodiment the means for enhancing the homogeneity of said parent solution comprises a moving plate.

In another embodiment, the invention relates to a device wherein said pumping devices comprise peristaltic pumps. The device according to the invention further comprises tubing guides for guiding the first and the second tube, said tubing guides being attached to said pumping devices.

In a preferred embodiment, the device according to the invention is provided within a lead shielding suitable for limiting the emission of ionizing radiation. This allows to reduce the exposure of the employees to the ionizing radiation emitted.

Another preferred embodiment concerns a device according to the invention further comprising valves for priming.

Practically, the third tube according to the device of the invention is provided with a fitting for connecting said third tube with said first and said second tube, as illustrated in figure 2, 3 and 4. The first tube is provided with a male luer lock 12, said male luer lock being protected with a stopcock 11, while the second tube and the third tube are provided with a female luer lock 14,16, said female luer lock being protected with a stopcock 13,15.

According to another embodiment, the device is provided with diluting solution, which comprises a physiological saline solution.

The device according to the invention is provided with a reservoir for receiving the individual doses of radiopharmaceutical solution which may comprises one or more syringe and/or vials or a combination thereof. Alternatively, the device of the invention may also be connected via the third tube to a patient.

The device according to the invention carries out a series of programmed sequences of tasks without manual intervention or assistance. The sequences are controlled from a desktop computer. During various stages of dose preparation automatic checks are initiated to prevent non-operation and system damage. The device according to the invention is suitable to dilute and dispense under sterile conditions all radiopharmaceutical solutions into sterile, evacuated vials according to safety guidelines that regulate the preparation of radioactive medicines. The automated dose dispenser according to the invention has been developed to completely replicate the manual syringe and vial filling process. The key benefits include reduced exposure to radioactivity and increased throughput while maintaining accuracy and repeatability. The computer-automated dispenser has been designed in a uniquely modular approach so that different preparations and procedures can be quickly accommodated by the addition of new modules and removal of redundant ones. Bar-codes may be used on all dispensed items for full traceability throughout the operation of the system.

The present invention is further illustrated with the following figures, but the invention is not intended to be limited thereto.

Referring to figure 1 a dose dispenser according to the invention is illustrated. The dose dispenser device comprises a first container containing a radioactive parent solution 4 and a second container containing a diluting solution 2. A tubing system is connected to the first and the second container, and to a reservoir 28 receiving the final dose of the radiopharmaceutical solution.

As represented on figures 1,2, 3 and 4 the tubing system consists of a flexible plastic supply, comprising three tubes, which are connected by means of a fitting 20. Each tube is provided with a luer lock 12,14, 16. Two tubes have a female luer lock 14,16 while one tube has a male luer lock 12. Three protection stopcocks, 11,13 and 15 protect the luer locks of the tubes. Further, the tubing system is clamped into a tubing guide 8 as illustrated on figure 3.

When removing the protection stopcocks 11 and 13, which protect the luer locks 12 and 14, respectively, the luer locks are connected to the container with parent solution 4 and the container with diluting solution 2 being a 0.9% NaCI solution, as shown on figure 1.

The luer lock 12 is connected onto a needle, which is poured in the radioactive parent solution 4. The luer lock 14 is connected to the container with diluting solution via a perfusion means 10, after removal of the protection cap 9 on the container with diluting solution 2. The luer lock 16 is connected to a single use three-way valve 23. One valve exit is connected to a reservoir 28 containing the final radiopharmaceutical solution. On figure 6-9, another type of valve exit can be connected to a syringe 6 to collect the final dose.

The tubing guides 8, wherein the tubes are clamped, are attached onto two peristaltic pumps 3 as illustrated on figures 1,4, 5,6, 7,8 and 9. The peristaltic pumps consist of a fixed, flat surface and a cam rotating around a shaft. As the cam rotates, parent or diluting solution enters in the tubing system. The solution essentially flows in only one direction thereby limiting flow re-circulation. A microporous filter for removing particulate matter from the solutions may be provided in the tubes.

Because the final radiopharmaceutical solution is to be injected into a living subject, it is extremely important that all parts of the system with which the liquid parent solvent or the

diluting solution come in contact are sterilized prior to use. In addition, certain other precautionary sterilizing features are included in the invention embodiment as depicted.

The tubes themselves, the fittings, the saline solution, valves distributors and the needles are only used a single time. All these components are already sterile or can be sterilized and they have to be replaced each time the parent solution is renewed. Also, the microporous filter is a microporous sieve having a pore size no greater than 0.22 microns in diameter. While a microporous sieve is not necessary where prior sterilizing techniques are carefully practiced, a microporous sieve is sometimes advisable as an added precaution to insure continuing sterility should inadvertent contamination exist. Bacteria which might otherwise survive prior sterilization techniques are thereby prevented from passing through the tubing system to the container final radiopharmaceutical solution.

An alternative embodiment of the invention is illustrated in figure 5. According to this embodiment the parent solution 4 is homogenized using a moving plate, for instance a mixer 1. The container containing the parent solution 4 is provided in a protection cabinet 18, in order to limit exposure to the radioactive parent solution 4. A software program calculates the required dilution of the parent solution with the diluting solution and controls the mixing movement of the parent solution, the pumping movement of the peristaltic pump and the dispensing of individual patient preparations. As shown on figure 5, the tubing system may be further provided with pinch valves 25 to stop the flow. The whole dispensing process is computer-controlled by means of computer equipment 26, provided with a programmable logic controller (PLC). The prepared radiopharmaceutical solution 28 can be disposed into a vial 5 or into a syringe 6. Syringe as well as vial may be comprised in a shielded cabinet 17 as represented on figure 5. A small container for diluting solution, f. e. a container of 100 ml, as well as a larger container for diluting solution, f. e. a container of 1 L may be used. As it should be understood from the figure, the radiopharmaceutical solution may be disposed in a multiple set of syringes or vial, which are not represented for ease of the representation.

When disposed in a vial 5, as illustrated in figure 6, the prepared radiopharmaceutical solution may also be extracted from this vial by means of a syringe 6, which is connected to this vial 5. In a preferred case, the vial 5 containing the radiopharmaceutical solution is provided in an ionization chamber 24. Lifting of the vial may also be computer regulated.

As shown on figure 8, the final radiopharmaceutical solution 28 may also be received in syringe 6, which can be lifted by means of a lift 29.

Other alternative embodiments of the invention are depicted in figure 7 and 9. These representations show the possibility to dispose the prepared radiopharmaceutical solution directly to a patient in need of such solution by means of a needle 7.

As illustrated in figure 9 a double single-use three-way valve 27 is used. This double three-way valve is connected to the tube, which provides the parent solution 4, to a syringe actuator 30 and to the tube, which provides the physiological solution 2. The outlet of the double valve 27 is provided with a tube, which carries a single three-way valve 23.

Through one valve exit of this single three-way valve 23 waste can be disposed, while the other valve exit may be connected either to a syringe 6, a final vial 5 or to a needle 7 which is applied directly to a patient. The whole system is controlled by means of a computer equipment 26 comprising a software program which calculates the required dilution of the parent solution, which controls a) the mixing movement of the moving plate or the mixer 1 in order to obtain a good homogenization of the parent solution, b) the action of the syringe actuator 30, c) the pumping movement of the peristaltic pumps 3, d) the action of the double three-way valve 27 and e) the dispensing of individual patient preparations into the preferred recipient, being a syringe 6, a vial 5 or needle 7 connected to the patient.

As it will be understood from the present invention the figures representing alternative embodiments of the invention comprise the feature of dispensing an individual dose of a radiopharmaceutical solution into the preferred recipient, being a syringe 6, a vial 5 or needle 7 connected to the patient at a specified speed.