68Ge/68Ga generator

Abstract

A .sup.68Ge/.sup.68Ga generator for a continuous production of a .sup.68Ga daughter nuclide, wherein the .sup.68Ge parent nuclide thereof is specifically adsorbed to an inorganic support material and wherein said .sup.68Ge parent nuclide continuously decays to .sup.68Ga by electron capture at a half-life of 270.82 d, wherein the inorganic support material is at least one oxide of a metal being selected from the group consisting of: Vanadium, Niobium and Tantalum. The use of at least one oxide of a metal being selected from the group consisting of: Vanadium, Niobium and Tantalum as an inorganic support material for the manufacture of a .sup.68Ge/.sup.68Ga generator for pharmaceutical purposes. With the inorganic support material of the present invention, it is possible to load .sup.68Ge/.sup.68Ga generators with up to 8000 MBq of .sup.68Ge (corresponding to 80 g Germanium).

Claims

1. A .sup.68Ge/.sup.68Ga generator for a continuous production of a .sup.68Ga daughter nuclide, wherein the .sup.68Ge parent nuclide thereof is specifically adsorbed to an inorganic support material and wherein said .sup.68Ge parent nuclide continuously decays to .sup.68Ga by electron capture at a half-life of 270.82 d, characterized in that the inorganic support material is at least one oxide particle size of 15 m to 300 m of a metal being Tantalum.

2. The generator according to claim 1, characterized in that the oxide is an oxide having the general formula (1):
M.sub.2O.sub.5(1), wherein M is Tantalum.

3. The generator according to claim 1, characterized in that the oxide is tantalum pentaoxide (Ta.sub.2O.sub.5).

4. The generator according to claim 3, characterized in that said Ta.sub.2O.sub.5 is present in its alpha- and/or beta-crystalline form.

5. The generator according to claim 1, characterized in that the oxide is obtainable by annealing a metal powder under oxygen atmosphere.

6. The generator according to claim 5, characterized in that the resulting oxide is Ta.sub.2O.sub.5.

7. The generator according to claim 1, characterized in that the .sup.68Ge parent nuclide is adsorbed to the oxide support material in form of .sup.68Ge(IV) cations.

8. The generator according to claim 1, characterized in that the .sup.68Ga is eluted from the generator with 0.01 to 0.1 M HCl.

9. The generator according to claim 8, characterized in that the breakthrough of .sup.68Ge is <10.sup.5%, at an initial activity of 4000 MBq.

10. The generator according to claim 8, characterized in that the elution yield of .sup.68Ga is >70% at an initial activity of 3000 MBq.

Description

DETAILED DESCRIPTION

(1) The present invention relates to the use of novel germanium specific adsorbents being selected from the group of vanadium oxide, niobium oxide and tanatalum oxide, particularly tantalum pentoxide (Ta.sub.2O.sub.5) in a .sup.68Ge/.sup.68Ga radionuclide generator. The chemically inert and stable adsorbents enable efficient adsorption of .sup.68Ge, efficient and stable desorption of .sup.68Ga, very low breakthrough of .sup.68Ge and efficient labelling of biomolecules with .sup.68Ga.

(2) Further features and advantages of the present invention will become evident from the following description of examples as well as from the drawings:

(3) FIG. 1 is a graphical representation of the percentage of breakthrough of .sup.68Ge as a function of cumulative elution volume of two .sup.68Ge/.sup.68Ga generators. Comparison between the current ITG GMP generator according to EP 2 439 747 B1 and the Ta.sub.2O.sub.5-based generator according to the present invention shows the significant difference in the levels of breakthrough of .sup.68Ge;

(4) FIG. 2 is a graphical representation of the elution yield of .sup.68Ga as a function of cumulative elution volume of two .sup.68Ge/.sup.68Ga generators. Comparison between the current ITG GMP generator according to EP 2 439 747 B1 and the Ta.sub.2O.sub.5-based generator of the present invention shows a large difference in the stability of elution yield of .sup.68Ga;

(5) FIG. 3 shows an HPLC chromatogram presenting the results from direct labelling with .sup.68Ga after 90 h of ingrowth time of a 1900 MBq .sup.68Ge/.sup.68Ga generator. The percentages of free non-labelled .sup.68Ga and labelled .sup.68Ga are 1.73% and 96.42%, respectively;

(6) FIG. 4A and FIG. 4B are images presenting scanning electron microscope (SEM) images of the surface structure of -Ta.sub.2O.sub.5 (FIG. 4A) and -Ta.sub.2O.sub.5 (FIG. 4B). From the images one can see the different surface characteristics indicating higher surface area of -Ta.sub.2O.sub.5 (FIG. 4A) suggesting higher capacity when applied in a .sup.68Ge/.sup.68Ga generator column;

(7) FIG. 5 represents an elution profile of .sup.68Ga of a .sup.68Ge/.sup.68Ga generator applied with Ta.sub.2O.sub.5 adsorbent. Initial .sup.68Ge activity of the generator was 1000 MBq;

(8) FIG. 6 represents a diagram of elution yield vs. elution volume of .sup.68Ga elution yields showing results greater than 70% (3 000 MBq);

(9) FIG. 7 represents a diagram of .sup.68Ge breakthrough, wherein values are below 10.sup.7%; and

(10) FIG. 8 represents an elution profile of .sup.68Ga of a .sup.68Ge/.sup.68Ga generator applied with Ta.sub.2O.sub.5 adsorbent. Initial .sup.68Ge activity of the generator was 4 000 MBq.

EXAMPLE 1: GENERATORS UP TO 1000 MBQ (27 MCI).SUP.68.GE

(11) The following synthesis method is described by way of example for the manufacture of tantalum pentoxide as the most preferred metal oxide in accordance with the present invention. However, those having average skill in the art will understand that the present synthesis method easily can be applied to the manufacture of the other preferred embodiments of the present invention, namely vanadium pentoxide and niobium pentoxide, particularly due to their close chemical properties.

Synthesis of Ta.SUB.2.O.SUB.5

(12) A synthesis method for the Ta.sub.2O.sub.5 adsorbent was developed by the applicant using two primary synthesis routes: hydrolysis route using tantalum pentachloride (TaCl.sub.5) as a starting material and annealing route using tantalum powder (Ta powder) as a starting material.

Hydrolysis Route

(13) Hydrolysis of TaCl.sub.5 was performed in water using controlled water/TaCl.sub.5 ratio. Temperature of water during the hydrolysis process was adjusted and kept stable in order to control the particle size of the final product Ta.sub.2O.sub.5. Annealing temperature of the tantalum hydroxide (Ta(OH).sub.5) was chosen based on the solid phase investigations in order to find the best performance for the adsorbent applied in a .sup.68Ge/.sup.68Ga radionuclide generator.

Annealing Route

(14) Oxidation of Ta powder was performed with starting material with selected particle size distribution. Annealing temperature of the Ta powder was chosen based on the solid phase investigations in order to find the best performance for the adsorbent applied in a .sup.68Ge/.sup.68Ga radionuclide generator.

Specifications of Synthesized Ta.SUB.2.O.SUB.5

(15) The specifications of the synthesized Ta.sub.2O.sub.5 applied in the radiopharmaceutical .sup.68Ge/.sup.68Ga generator include the following criteria: annealing temperature, particle size distribution, distribution factor between .sup.68Ge and adsorbent (K.sub.D), and desorption (elutability) of .sup.68Ga. The criteria are summarized in Table 2 below.

(16) TABLE-US-00002 TABLE 2 Specifications of synthesized Ta.sub.2O.sub.5. Specification Criterium Annealing temperature 600-1350 C. Distribution factor (K.sub.D) 2000-20000 mL/g Elutability of .sup.68Ga 65% Particle size distribution 10-200 m

Characterization of Ta.SUB.2.O.SUB.5 .Adsorbent

(17) During the development of synthesis of the tantalum pentoxide adsorbent different parameters correlating to adsorption and desorption properties of .sup.68Ge and .sup.68Ga, respectively, were investigated (Table 3). These parameters included crystal structure and surface morphology of the Ta.sub.2O.sub.5, surface area and particle size distribution. The results obtained by radiochemical analysis for .sup.68Ge (distribution factor (K.sub.D) and capacity) and for .sup.68Ga (elutability) were correlated by the observations and results obtained by analytical techniques such as x-ray diffraction (XRD) applied for crystal structure analysis, scanning electron microscopy (SEM) (FIG. 4) applied for surface morphology investigations, surface area determination (Brunauer-Emmet-Teller (BET)) and determination of particle size distribution.

(18) TABLE-US-00003 TABLE 3 Correlation between the different specifications of the synthesized Ta.sub.2O.sub.5 adsorbent material. Annealing Particle size temperature distribution K.sub.D for .sup.68Ge Elutability Adsorbent ( C.) (m) (mL/g) of .sup.68Ga -Ta.sub.2O.sub.5 800-1350 10-200 137992-240964 7.2% 101219-140377 37% 18691-19522 47% .sup.7878-8905 *.sup.1 .sup.69% *.sup.1 -Ta.sub.2O.sub.5 1500 10-200 779-870 67% 567-615 68% *.sup.1 Particles of <8 m diameter separated

(19) Tetravalent germanium exists in generator-relevant solution pH (0.05 M HCl) and Ge concentrations ([Ge.sub.total]<0.005 M) in the form of germanic acid (Ge(OH).sub.4) [12,13]. In these conditions germanium binds with hydroxyl groups on the surface of tantalum pentoxide [14]. Experiments have indicated a clear positive correlation between small particle size and high surface area to efficient adsorption of .sup.68Ge. On the other hand, small particle size has a negative effect on the efficiency of elutability of .sup.68Ga. That is why the main goals in the development of the synthesis method for Ta.sub.2O.sub.5 have been to minimize the formation of small particles (<10 m), and to increase the surface area of Ta.sub.2O.sub.5 particles. In the FIG. 4 one can see the difference in the surfaces of the two crystalline forms of Ta.sub.2O.sub.5: the particles formed of -Ta.sub.2O.sub.5 (FIG. 4A) have surface covered with caves and formations formed during the aggressive chemical conditions of hydrolysis; thus providing higher surface area and higher K.sub.D and capacity for .sup.68Ge compared to the particles of -Ta.sub.2O.sub.5 (FIG. 4B) where these morphological structures have melted due to high annealing temperature. On the other hand, the glossy surface characteristics of the -Ta.sub.2O.sub.5 effects provide better elutability properties for .sup.68Ga.

(20) In conclusion: the aim has been to develop a method of synthesis for Ta.sub.2O.sub.5 adsorbent with the ideal equilibrium between efficient adsorption of .sup.68Ge (shelf life) and efficient elutability of .sup.68Ga (elution yield).

(21) A batch of germanium specific adsorbent was synthesised by following the hydrolysis route:

(22) Tantalum pentachloride (TaCl.sub.5) was mixed with hot water (80 C., solid/liquid ratio 20 g/L) to produce tantalum hydroxide (Ta(OH).sub.5), which was annealed under 900 C. over 24 h in order to form crystalline tantalum oxide (Ta.sub.2O.sub.5). After isolation of particles with a size range of 10 m-200 m the final material was used as an adsorbent for the .sup.68Ge/.sup.68Ga generators.

(23) Two generator columns were filled with a known amount of the adsorbent (8 g). The columns were loaded with a known amount of .sup.68Ge (1000 MBq, 2000 MBq) and stable Ge (total mass of Ge=80 g). The radionuclide generators were produced under GMP-conditions.

(24) The .sup.68Ge/Ga generators were subjected to an elution program and the critical parameters were followed. At the current stage of the elution program the following values related to the critical parameters are valid: Current total cumulative elution volume: 700 mL (1000 MBq), 400 mL (2000 MBq) Elution yield of .sup.68Ga: >65%, stable Currently: 70% (1000 MBq), 73% (2000 MBq) (FIG. 2) Elution volume: 6 mL (FIG. 6) Breakthrough of .sup.68Ge: <10.sup.6% (level of Ph. Eur.: 10.sup.3%) Currently: 10.sup.7% (1000 MBq), 410.sup.7% (2000 MBq) (FIG. 1) Labelling efficiency: >96% after 90 h of ingrowth period via direct elution (.sup.68Ga-DOTA-TOC) (FIG. 3).

Critical Quality Parameters: Breakthrough of .SUP.68.Ge and Elution Yield of .SUP.68.Ga

(25) In general, some factors related to the properties of the adsorbent of .sup.68Ge/.sup.68Ga generator affect on the critical quality parameters of .sup.68Ga eluate. Low chemical stability of adsorbent increases the breakthrough of .sup.68 in the conditions of high radiolytical stress. Moreover, during the shelf life of a generator .sup.68Ge activity zone moves via elutions along the adsorbent column making germanium prone to be partly diffused inside the crystal lattice defects of metal oxides or the network of carbon chains of pyrogallol-derivatives and silica. These diffusion phenomena are likely to be factors which cause the decrease of elution yield of .sup.68Ga via elutions being typical for the prior art .sup.68Ge/.sup.68Ga generators on the market.

(26) Tantalum pentoxide was originally chosen to be used as adsorbent for two main reasons: It is chemically inert and stable material, which makes it suitable to be applied in conditions of high radiolysis and surprisingly yielding low breakthrough of .sup.68Ge (FIG. 1). Moreover, the fact that the tantalum cation is (primarily) in pentavalent oxidation state was regarded to be beneficial for the .sup.68Ga elution yield stability and preventative against the diffusion of tetravalent germanium into the crystal lattice of the Ta.sub.2O.sub.5 (FIG. 2). Evidence of these properties, i.e., chemical stability and nature can be seen in the FIGS. 1 and 2 presenting the behavior of breakthrough of .sup.68Ge and elution yield of .sup.68Ga in the GMP generator and Ta.sub.2O.sub.5 generator in function of cumulative elution volume, respectively.

Critical Quality Parameter: Labelling Properties of Generator

(27) Labelling properties of a radiopharmaceutical .sup.68Ge/.sup.68Ga generator applied with synthesized Ta.sub.2O.sub.5 adsorbent were tested by a method based on the monograph of European Pharmacopoeia [11 ]. The test was performed for .sup.68Ga eluate eluted from a generator with the nominal .sup.68Ge activity of 1900 MBq and ingrowth time (time of no elutions) of 90 hours. The aim of the test was to demonstrate the stability of the Ta.sub.2O.sub.5 adsorbent against radiolysis even during a longer period of time of no elutions. The results obtained by high-pressure liquid chromatography (HPLC) from the direct labelling were over 96% yield of labelled product. This clearly demonstrates the extensive stability of the Ta.sub.2O.sub.5 adsorbent used in a .sup.68Ge/.sup.68Ga generator, and indicates that no rinsing after weekends is necessary in order to yield a fully functional generator for the use of radiolabelling (FIG. 3).

EXAMPLE 2: GENERATORS GREATER THAN 1850 MBQ (50 MCI).SUP.68.GE

(28) Generator column was filled with known amount of the adsorbent (8-9 g). The column was loaded with known amount of .sup.68Ge (4000 MBq) and no stable Ge was added (total amount of Ge was calculated by specific activity of Ge-68 to 44 g). The .sup.68Ge/.sup.68Ga generator was subjected to an elution program and the critical parameters were followed. At the current stage of the elution program the following values related to the critical parameters are shown in FIGS. 6, 7, and 8:

(29) In particular, FIG. 6 shows a diagram in which values of elution yield in % are plotted against the elution volume in ml, showing .sup.68Ga elution yields of greater than 70% (3000 MBq).

(30) FIG. 7 shows that the breakthrough values for .sup.68Ge are less than 10.sup.7%.

(31) Finally, FIG. 8 represents an elution profile of .sup.68Ga of a .sup.68Ge/.sup.68Ga generator applied with the Ta.sub.2O.sub.5 adsorbent. The initial .sup.68 Ge activity of the generator was 4000 MBq.

(32) The Generator showed .sup.68Ga yields >3000 MBq. Typical Labelling procedures with common .sup.68Ga PET tracers, such as PSMA-11 (HBED-CC) and DOTATATE showed results of 55 mCi ([Ga-68]Ga-HBED-CC) and 45 mCi ([Ga-68 ]Ga-DOTATATE) at end of Production (end of production is typically 30 min to 60 min after Generator elution).

(33) Based on calculation of the specific activity of 100 GBq/mg .sup.68Ge and the nominal total applicable Germanium amount on 8-9 g Ta.sub.2O.sub.5 Generator columns, it is possible to load generators with 8000 MBq of .sup.68Ge (corresponds to 80 g Germanium).

(34) Similar elution profiles, breakthrough values, yields (data not shown) as specified in Examples 1 and 2 could be achieved when replacing the Ta.sub.20.sub.5 by its corresponding oxides Nb.sub.20.sub.5 and V.sub.20.sub.5. The synthesis thereof follows essentially the same routes as described in Example 1 above.

(35) With the present invention, the clinical demand of a radiopharmaceutical grade .sup.68Ga in sufficient quantity and reliable quality can be fulfilled.

REFERENCES

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