HK1190818B - Method for producing carrier-free highly pure 177lu compounds and carrier-free 177lu compounds - Google Patents

Description

Production of high purity without carrier addition177Method for the production of Lu compounds and the addition of Lu compounds without a carrier177Lu compounds

Technical Field

The invention relates to the production of a substantially carrier-free added high purity for pharmaceutical and/or diagnostic purposes according to claims 1 and 10¹⁷⁷Method of Lu compounds, and the carrier-free addition of claim 12¹⁷⁷A Lu compound.

Background

Because of the promising basic clinical methods of radionuclide therapy and radionuclide diagnostics, the world is dealing with reactor nuclides¹⁷⁷The demand for Lu is increasing. As having a shorter half-life T_1/2A 6.71 day low energy β emitter,¹⁷⁷lu constitutes an excellent vehicle for the specific deposition of large amounts of energy in small volumes. These physical properties are used to a large extent in the form of radioimmuno-radionuclide therapy and peptide receptor radionuclide therapy in oncology, in particular for the therapy and diagnosis of tumors.

As is well known in the art,¹⁷⁷lu can be produced via the following nuclear reaction:

the direct method comprises the following steps:¹⁷⁶Lu(n，y)¹⁷⁷Lu(1)

the indirect method comprises the following steps:¹⁷⁶Yb(n，y)¹⁷⁷Yb→¹⁷⁷Lu(2)

the nuclear reaction (1) constitutes¹⁷⁶Neutron capture reaction of Lu, which ultimately produces carrier-added¹⁷⁷Lu (with addition of Carrier)¹⁷⁷Lu[¹⁷⁷Luc.a.]) And therefore limited product quality in the form of significantly lower specific activity. As a result, it is in use¹⁷⁷The activity range per a certain number of biomolecules is significantly reduced during the labeling of the biomolecules by Lu. This leads to poor therapeutic efficacy or side effects in a limited number of receptors on the tumor surface. By passing¹⁷⁶Irradiation of Lu, in addition to the production of long-lived metastable radionuclides^177mLu(T_1/2160.1 days), which is undesirable in terms of pharmaceutical use and radiation protection. Depending on the parameters of the radiation, it is,^177mlu account for¹⁷⁷The ratio of Lu activity may be up to 0.1%. Such contamination must be considered in view of its application to the human body and in view of the overall high activity produced. Within the therapeutic range, due to the long half-life of the nuclide and its useRenal excretion in patients treated with Lu isotopes,^177mthe risk of Lu release into the environment is permanently increased. Thus, consumers in hospitals are faced with the problem of safe handling and disposal of long-lasting nuclide residues, for which hospital conventional radioactive waste storage is almost impossible to solve.

As mentioned at the outset, with addition of a carrier¹⁷⁷Lu is currently available on the market, it being added in contrast to non-carriers¹⁷⁷Lu has various disadvantages. However, since so far¹⁷⁷Luc.a. is more readily available and, despite its drawbacks, is still preferred by many hospitals.

Are currently available on the market¹⁷⁷Lu is sold by essentially three suppliers. All suppliers were obtained by the same method, i.e. directly from the above-mentioned nuclear reaction (1)¹⁷⁶Lu production¹⁷⁷Lu。

This leads to the problems mentioned hereinbefore.

Thus, a more attractive, pharmaceutically and commercially useful, but technically demanding option is to produce non-carrier additions by an indirect nuclear reaction (2)¹⁷⁷Lu. Such nuclear reactions can be used, for example, on high flux neutron sources to produce carrier-free¹⁷⁷Lu. By using¹⁷⁶Yb irradiation to produce short-lived radioisotopes¹⁷⁷Yb(T_1/21.9 hours), it decays to¹⁷⁷Lu。

The nuclide required in this case¹⁷⁷Lu is not a target nuclide¹⁷⁷The element of Yb, but a nuclide of a different element, can thus be separated chemically in a non-carrier-added form (non-carrier-added)¹⁷⁷Lu[¹⁷⁷Lun.c.a.]) Provided that the Yb nuclide can be quantitatively separated. Because of the nuclide¹⁷⁷Decay of Yb does not produce^177mLu, thus producing a compound having very high radioactive isomeric and radionuclide purity¹⁷⁷Lu。

However, a disadvantage of using this strategy is thatThe Yb (plenty) has to be isolated radiochemically¹⁷⁷Lu (micro) system. Because the target nuclear species and the target nuclear species are two adjacent elements in the lanthanide, separation is still very difficult due to their chemical similarity.

One solution to the above separation problem can be found in patent US6,716,353B1, which describes using an indirect method according to equation (2) above¹⁷⁷Lun.c.a. is separated from ytterbium, thus producing a material with high specific radioactivity¹⁷⁷Lu. In this process, ytterbium was first adsorbed by LN resin (LN resin of Eichrom) containing di- (2-ethylhexyl) orthophosphoric acid (HDEHP) as an extractant by using a medium concentration of inorganic acid. According to the method of US6,716,353B1, ytterbium was first eluted from a column containing LN resin by using a medium concentration of hydrochloric acid, and then obtained by using a higher concentration of hydrochloric acid¹⁷⁷Lu。

Due to trace amount¹⁷⁷The fact that Lu is separated from a large amount of ytterbium shows the disadvantage of this prior art method that according to US6,716,353B1, the micro-components are eluted first from the very large amount of residue present. Since ytterbium spreads as a tail of the peak end as a result of the extraction chromatography system, this process is repeated several times to obtain¹⁷⁷The corresponding quality of Lun.c.a. due to the system inevitably remaining in the Lu eluate,¹⁷⁶the residual amount of Yb cannot be ignored. Furthermore, according to the prior art of US6,716,353B1, only activity values in the MBq range were obtained. The method disclosed in US patent 6,716,353B1 is extraction chromatography, which means that the extractant is adsorbed on the surface of the column material, which naturally follows the desired one¹⁷⁷Lu is partially eluted together, thus additionally chemically contaminating the product. In addition, in order to elute¹⁷⁷Lu, which requires large amounts of concentrated hydrochloric acid in the subsequently present product. Moreover, the process disclosed at US6,716,353B1 is very time consuming, requiring more than 16 hours of processing time on a single column. Production therefore lasts several days with the need for repeated steps.

Thus, as to¹⁷⁷Lu nuclide quality notThe often high medical requirements make the manufacturing process and the resulting feasibility more difficult.

However, radionuclides¹⁷⁷The successful use of Lu is determined by the specific activity of the nuclide obtained by production (Bq/mg) and its purity. A high specific radioactivity of the radionuclide is required to achieve as high a specific radioactivity as possible and thus an optimal amount of application of the corresponding radiopharmaceutical. If high specific radioactivity and purity are not achieved, adverse effects on the production of the radiopharmaceutical or on the quality of the radiopharmaceutical itself may result, among other problems.

Disclosure of Invention

Accordingly, based on the closest prior art US6,716,353B1, it is an objective of the present invention to provide a high purity for manufacturing pharmaceutical purposes with non-carrier additions available in commercial grade¹⁷⁷Lu (unsupported addition [ n.c.a.]¹⁷⁷Lu).

With regard to the method, the object is solved by the features of claims 1 and 10, while with regard to the product, the object is solved by the features of claim 12.

In particular, the invention relates to radiation from thermal neutrons¹⁷⁶Production of substantially carrier-free added high purity in Yb compounds for therapeutic and/or diagnostic purposes¹⁷⁷Method for producing Lu compounds, comprising predominantly Lu compounds in a mass ratio of approximately 1:10²To 1:10¹⁰Nuclides of¹⁷⁷Lu and¹⁷⁶the neutron radiation end product of a mixture of Yb is used as a substrate, wherein the water-insoluble substrate can be converted into a soluble form via a mineral acid and/or elevated temperature, and wherein the method comprises the steps of:

a) by dissolving in mineral acid and containing the mass ratio of about 1:10²To 1:10¹⁰Is/are as follows¹⁷⁷Lu and¹⁷⁶loading a substrate of Yb into a first column packed with a cation exchange material; exchanging protons of the cation exchange material for ammonium ions, usingNH₄A Cl solution; and washing the cation exchange material of the first column with water;

b) connecting the outlet of the first column to the inlet of a second column also filled with cation exchange material;

c) a gradient of water and chelating agent was applied from 100% H at the inlet of the first column₂Start with O to 0.2M chelating agent, eluting from the first and second columns¹⁷⁷A Lu compound, said chelator selected from α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA and ammonium ions;

d) determining radiation dose at the exit of the second column to identify¹⁷⁷Elution of the Lu compound; the first from the second column outlet¹⁷⁷Collecting the Lu eluate in a container; and protonating the chelating agent for use with¹⁷⁷Inactivation of the chelating agent of the Lu ion-forming complex;

e) by continuously conveying the acidity of step d)¹⁷⁷Loading the Lu eluate to the inlet of a final column packed with a cation exchange material; washing the chelating agent with dilute mineral acid at a concentration of less than about 0.1M; by washing the cation exchange material of the final column with varying concentrations of mineral acid ranging from about 0.01 to 2.5M¹⁷⁷Removing trace amounts of other metal ions from the Lu solution;

f) eluting from the final column with a high concentration of mineral acid of about 1 to 12M¹⁷⁷Lu ion; will have high purity¹⁷⁷The Lu eluate is collected in an evaporation unit and the mineral acid is removed by evaporation.

The described embodiments may be repeated any number of times by repeating the separation method using α -hydroxyisobutyrate as the chelating agent and using the column system, as described by way of example in the following embodiments:

an alternative embodiment of the method according to the invention is a method as follows: from being irradiated by thermal neutrons¹⁷⁶Production of high purity in Yb compounds for pharmaceutical purposes with essentially carrier-free addition¹⁷⁷Lu compound, mainly containing the same in a mass ratio of about 1:10²To 1:10¹⁰Nuclides of¹⁷⁷Lu and¹⁷⁶the neutron radiation end product of a mixture of Yb is used as a substrate, wherein the water-insoluble substrate is converted into a soluble form via a mineral acid and/or elevated temperature, and wherein the method comprises the steps of:

a) by dissolving in mineral acid and containing the mass ratio of about 1:10²To 1:10¹⁰Is/are as follows¹⁷⁷Lu and¹⁷⁶loading a substrate of Yb into a first column packed with a cation exchange material; exchanging protons of the cation exchange material for ammonium ions, wherein NH is used₄A Cl solution; and washing the cation exchange material of the first column with water;

b) connecting the outlet of the first column to the inlet of a second column also filled with cation exchange material;

c) a gradient of water and chelating agent was applied from 100% H at the inlet of the first column₂A chelating agent selected from the group consisting of α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ions, starting with O to 0.2M;

d) determining radiation dose at the exit of the second column to identify¹⁷⁷Elution of the Lu compound; the first from the second column outlet¹⁷⁷Collecting the Lu eluate in a container; and protonating the chelating agent for use with¹⁷⁷Inactivation of the chelating agent of the Lu ion-forming complex;

e) continuous conveying of the acidity of step d)¹⁷⁷Lu eluate to the inlet of the third column packed with cation exchange material, due to the acidic loading¹⁷⁷Lu eluate, the cation exchange material being present in protonated form; exchanging protons of the cation exchange material for ammonium ions, wherein NH is used₄A Cl solution; and washing the cation exchange material of the third column with water;

f) connecting the outlet of the third column with the inlet of a fourth column filled with a cation exchange material;

g) a gradient of water and chelating agent was applied from 100% H at the inlet of the third column₂A chelating agent selected from the group consisting of α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ions, starting with O to 0.2M;

h) measuring the radiation dose at the exit of the fourth column to identify¹⁷⁷Elution of the Lu compound; second from the outlet of the fourth column¹⁷⁷Collecting the Lu eluate in a container; and protonating the chelating agent for use with¹⁷⁷Inactivation of the chelating agent of the Lu ion-forming complex;

i) by continuously conveying the acidity of step h)¹⁷⁷Loading the Lu eluate to the inlet of a final column packed with a cation exchange material; washing the chelating agent with dilute mineral acid; by washing the cation exchange material of the final column with varying concentrations of mineral acid ranging from about 0.01 to 2.5M¹⁷⁷Removing trace amounts of other metal ions from the Lu solution;

j) eluting from the final column with a concentrated mineral acid of about 1M to about 12M¹⁷⁷Lu ion; will have high purity¹⁷⁷The Lu eluate is collected in an evaporation unit and the mineral acid is removed by evaporation.

Although the prior art has disclosed for a long time the basic principle of separating lanthanides, and in particular trivalent lanthanides, on a cation exchange and complexation basis, according to "Lehrbuchhder Anorganischen Chemie" (textbook of inorganic chemistry), Deguyen-Prov. (Publishers Walter Gruyter), Berlin-New York, 102 th edition, 2007, pages 1932 to 1933 of Hollemann-Wieberg, it only applies to the presence of a similar amount of lanthanides, but not to the mass ratios in which the highest purity lanthanide cations desired have to be separated from the remainder in mass-relation to the million times the mass of the other lanthanides. Furthermore, according to Hollemann-Wieberg, even from the prior art, in particular from FIG. 393, it can be seen that the selectivity between Lu and Yb alone is not sufficient, since in the case of mixtures of the lanthanides Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, the peaks of the lanthanides when eluted from the ion exchange resin Dowex-50 with ammonium α -hydroxyisobutyrate overlap significantly.

In contrast to the processes described in the prior art, the present invention for the first time makes it possible to produce industrially relevant quantities of high purity non-carrier added¹⁷⁷Lu, and can thus be subjected to further direct processing, such as coupling to biomolecules to make radiopharmaceuticals. This is due in particular to the fact that: to the obtained¹⁷⁷The Lu product gives requirements on purity and sterility, and the method completely conforms to EU-GMP guidelines.

A particular advantage of the manufacturing method according to the invention is that ytterbium can be processed in gram quantities. This allows tens of thousands of megabytes (TBq) to be produced per production run¹⁷⁷Lun.c.a. The production method thus for the first time enables the production of milligram quantities of radionuclides¹⁷⁷Lun.c.a, which is suitable for use in nuclear medicine and diagnostics due to its own chemical and radiochemical purity.

A further advantage of the process according to the invention is that it can be completed in about 10 hours to obtain the final product.

This is caused by several factors. On the one hand, many processes are operated simultaneously and therefore, by means of the front-end column systems VS1 and VS2 (see fig. 1) used in the preferred embodiment, it is possible to start each subsequent separation process even while still operating the preceding separation. Furthermore, the gradient of the pump can be optimized to¹⁷⁷High separation factor and short retention time of Lu.

If, for example, a pre-column is used, it is thus possible to load the cation exchange material with an acidic or acidified solution which is not substantially optimal for the separation. Thus, complexing treatment steps such as evaporation or neutralization can be omitted, at least to a large extent. Furthermore, since no aggressive vapors are generated by the additional evaporation step, corrosion of the production equipment is avoided. In addition, the risk of contamination is clearly reduced. By washing the pre-column, contaminants can be removed from the system and, if desired, also appropriately disposed of or recycled.

The use of a pre-column generally improves the separation from Yb¹⁷⁷Lu and by using a final purification step of other columns, the quality is further improved, since thereby it is possible to obtain¹⁷⁷Even traces of other metals are removed from the Lu product. Furthermore, the process according to the invention makes it possible to provide an already sterile end product which is furthermore practically non-toxic and can be used directly for further radiopharmaceutical processing, for example coupling to proteins.

These dimensions are well known to those skilled in the art with respect to the geometric dimensions of the pre-column and separator column and their dimensional ratios to each other.

Preferably, the method according to the invention is carried out according to the following alternative embodiments: between steps d) and f) according to claim 1 additionally the following steps are performed:

d.1) continuous conveying of step d) and simultaneous acidification¹⁷⁷Lu eluate to the inlet of the third column packed with cation exchange material, due to the acidic loading¹⁷⁷Lu eluate, the cation exchange material being present in protonated form; exchanging protons of the cation exchange material for ammonium ions, wherein NH is used₄A Cl solution; and washing the cation exchange material of the third column with water;

d.2) connecting the outlet of the third column with the inlet of a fourth column filled with cation exchange material;

d.3) applying a gradient of water and chelating agent from 100% H at the inlet of the third column₂Chelating agent starting from O to 0.2M, thereby eluting from the third and fourth columns¹⁷⁷A Lu compound, the chelating agent selected from the group consisting of α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA and ammonium ion;

d.4) determining the radiation dose at the outlet of the fourth column for identification¹⁷⁷Elution of Lu Compounds(ii) a Introducing a second one from the outlet of the third column¹⁷⁷Collecting the Lu eluate in a container; and protonating the chelating agent for use with¹⁷⁷The chelating agent of the Lu ion forming complex is deactivated.

The advantage of this method is that, in the case of two pairs of columns, which are each connected in series in the direction of flow, a front-end column and a separation column are provided in each case. After passing through a second pair of pre-column and separation column, double purified¹⁷⁷The Lu eluate then reaches the final separation column and still releases other traces of metals. Furthermore, the pre-column/separation column concept has the advantage that it thus makes it possible to achieve column applications of acidic and acidified solutions, respectively, in which and per se only partially suitable for separation. In practice, the clean separation is only carried out in the separation column, i.e. for example in the second and/or fourth column. A further advantage is that the processing time is reduced, since loading of smaller fore-pillars may be faster.

Of course, it is also well known to those skilled in the art that more than two pairs of pre-columns/separation columns may also be used if desired.

If elution is carried out in steps d) and d.4)¹⁷⁷After the Lu compound, the first and second columns and the third and fourth columns are washed with a higher concentration of chelating agent to elute Yb ions from the cation exchange material, and the obtained product mainly contains¹⁷⁶The Yb eluate of the Yb ions is collected separately for the purpose of reusing it as a manufacturing product¹⁷⁷Lu, then, is advantageous for recycling the Yb material used and for shortening the treatment time thereof.

For acidification¹⁷⁷The following mineral acids of the Lu eluate have proven suitable: HNO₃、HCl、H₂SO₄HF, and organic acids such as acetic acid.

If it is to be made from water-insoluble¹⁷⁶From Yb oxide¹⁷⁷Lu compounds, it is then possible and preferred to convert those oxides into a form which is soluble in water, for example byUsing 1M to 12M HNO₃Or other oxidizing acids.

Typically, HNO is used at acid concentrations of 0.01M to 2M₃HCl, or other inorganic and/or organic acids to load the cation exchange material.

The cation exchange material is selected from: macroporous cation exchange resins and gel-like cation exchange resins based on polystyrene or on other organic polymers, and also cation exchange resins based on silicates, have proven particularly suitable.

In contrast to the prior art, it is preferred to use gram quantities of Yb substrate and to produce quantities up to milligrams¹⁷⁷Lu。

In general,¹⁷⁷lu has a radiation dose of several TBq, and a lutetium content of about 3.9TBq per mg of Lu is available¹⁷⁷Specific activity of Lu, which is close to per mg¹⁷⁷4TBq of Lu¹⁷⁷Theoretical physical limit of Lu.

For reasons of radioprotection and for reasons of pharmaceutical legislation, the invention is implemented in a hot chamber of at least a class C clean room according to EU-GMP regulations.

To ensure carrier-free addition¹⁷⁷Pharmaceutical quality of the Lu product and approval for manufacture, the chromatographic apparatus implementing the method of the invention is transferred to the environment of a clean room. Furthermore, the use of a hot cell makes it possible to implement the method of the invention in the form of a semi-automatic or fully automatic process.

Finally, the process according to the invention produces a carrier-free addition¹⁷⁷Lu Compound (A)¹⁷⁷Lun.c.a), said¹⁷⁷The Lu compound is obtained according to the process of at least one of claims 1 to 11.

Without carrier addition¹⁷⁷The particular advantage of the Lu compound is that it is suitable for direct use in radiopharmaceutical applications, i.e. without further purification and/or disinfection.

Using according to the invention¹⁷⁷The compound of Lu is a compound of Lu,more than 400MBq per μ g peptide or polypeptide or other biomolecule can be achieved¹⁷⁷Labeling ratio of Lu.

According to the invention, without carrier addition¹⁷⁷An additional advantage of the Lu compound is that it can be used to label peptides, polypeptides, antibodies or other biomolecules even weeks after it has been manufactured. This is due in particular to its high specific radioactivity and to its high radioisotope and chemical purity.

Using the process according to the invention, it is possible for the first time to achieve n.c.a.on an industrial mass production scale¹⁷⁷Daily production of Lu.

Further advantages and features will appear from the description of the embodiments and the accompanying drawings.

Drawings

FIG. 1 shows a schematic structure of an exemplary apparatus for carrying out the method of the present invention;

FIG. 2 shows the recording at the exit of column S1 in FIG. 1¹⁷⁷Column chromatography for Lu and ytterbium separation;

FIG. 3 shows the recording at the exit of column S2 in FIG. 1¹⁷⁷Column chromatography for Lu and ytterbium separation;

fig. 4 shows c.a in comparison according to the prior art.¹⁷⁷Lu and the carrier-free addition obtained according to the invention¹⁷⁷Lu end product (n.c.a)¹⁷⁷Lu) in a gas phase.

Detailed Description

An example structure of an apparatus for carrying out the method of the invention is described hereinafter, with reference to fig. 1:

for radiation protection reasons, the method is carried out in an environment shielded by lead and/or plexiglas. This may be a hot chamber or a different suitable system. Considering the fact that the product is used as a pharmaceutical, the environment is classified into corresponding cleanliness classes according to the requirements of pharmaceutical manufacturing (drug manufacturing quality management practice, GMP of EU). In this case, the ambient environment in the hot chamber must comply with class C or higher.

The hot cell has a suitable two-door system to the environment, in which auxiliary systems for production, such as HPLC pumps, syringe pumps or other delivery systems, and control systems are housed.

The system has several individual components such as chromatography columns (VS1, S1, VS2, S2 and S3), flasks (F1 to F6) and pumps (P1 to P7) connected to each other by capillaries and valves.

Depending on its function or according to other operating principles, the pump may be configured as a vacuum pump, a syringe pump, an HPLC pump, a peristaltic pump. In the present embodiment, the pumps (P1) and (P2) are configured as HPLC pumps. They deliver H at different concentrations (from 0.01M to 10M) and flow rates (from 0.05 ml/min to 100 ml/min)₂O, HIBA and NH₄And (4) Cl. Pumps (P3), (P4), (P5), (P6) deliver other reagents such as HCl, HNO at different concentrations (from 0.01M to 10M) and flow rates (from 0.05 ml/min to 100 ml/min)₃、H₂O and air. In a preferred arrangement, the pumps P3 to P6 are syringe pumps or plunger pumps. However, additional valves may be implemented to form the pump system when configuring the syringe pump. The pump 7(P7) is a vacuum pump configured to be able to apply a variable negative pressure (from 1 mbar to 1000 mbar) to the system.

The component labeled (N2) (which itself is not numbered) is an inert gas source, preferably nitrogen and argon, by which a pressure of 0.1 bar to 5 bar or more can be applied to the system depending on the system configuration.

The assembly (1) is configured to split the ampoule and additionally convert ytterbium oxide to ytterbium nitrate. In this embodiment, two separate functions are designed as an integrated function.

The assembly (2) is an evaporation unit for evaporating the lutetium solution to dryness. The component (3) is a system for containing the final product, for example a glass vial. Within the scope of functional integration, the components (2) and (3) can be configured as one structural component.

All valves in this embodiment are depicted as being reversible in each direction. The position of the valves is chosen so that the number thereof is minimized. From fig. 1, it will be apparent to those skilled in the art that other valve configurations, particularly for the engagement and disengagement functions, are readily conceivable.

Flasks (F1), (F2), (F3), (F4), (F5), (F6) are containers for receiving the solution. Preference is given to glass flasks whose volume is adapted to the requirements of the process according to the invention. Especially for larger volumes, the preferred embodiment is a plastic container.

The column system exemplarily shown in the preferred embodiment comprises so-called front columns (VS1) and (VS2) through which the loading takes place. The main columns (S1) and (S2) forming the actual separation columns in the embodiment are connected to the front-end column, so that each of the pair columns (VS1) and (S1) or (VS2) and (S2) can be connected to the column system.

Regardless of the actual configuration, an overall liquid flow diagram for an exemplary device embodying the present invention is depicted in FIG. 1, as well as the configuration in the hot chamber. In a preferred embodiment, the components (2) and (3) are positioned in separate screening devices in order to fill the subsequent process steps with the product desired by the customer¹⁷⁷The amount of Lu can be all in one system. For logical reasons, the components (2) and (3) are integrated in one system. An additional preferred embodiment is to have the assembly (3) in a separate shielded unit so that the whole process is carried out in one unit, while the vial (3) used only to receive the product is located in a more pharmaceutically complex environment.

In order to control the process, activity sensors are used in the examples, each located at the end of columns (S1), (S2) and (S3) to monitor the separation process.

Examples

The invention is thatIrradiated by reactor¹⁷⁶Extraction from Yb¹⁷⁷A method for producing lun.c.a. For this purpose, the irradiated ampoule is opened in an ampoule cup and transferred into a conversion vessel (F1).¹⁷⁶Yb may exist as an insoluble oxide. To extract in the radiation process¹⁷⁷Lu, the substrate must be converted to a soluble form. In this example, this can be achieved by using 1M to 12M HNO₃This can be done by heating if desired.

By adding HNO₃Diluted to a lower acid concentration of between 0.01M and 1.5M, the solution can be loaded onto a pre-column system (VS1) as a first column. By loading, the column material in the pre-column system, i.e. the polystyrene-based macroporous cation exchanger, is converted into negative H for the separation⁺Form (protonated form). By using NH₄Cl, conversion of the column material of the front-end column system into its NH₄ ⁺Form (a). Subsequently, the front-end column system VS1 was washed with water and connected to the separation column S1 as a second column.

Separation was performed at high flow rates (10-50 ml/min) by pump P1 for this purpose, a α -hydroxy-isobutyrate (HIBA) and water gradient, used as chelating agent in the examples, was optimized for separation in the VS1/S1 system, set on 100% water to 0.2M HIBA, and separation was performed in a pre-column system VS1 and separation column S1¹⁷⁷Lu, the eluate was collected in collection flask F2.

In FIG. 2¹⁷⁷The separation of Lu and ytterbium is described as chromatography. The ordinate represents the force applied to the column respectively¹⁷⁷The elution amounts% of Lu and ytterbium, while the abscissa indicates the retention time in minutes. The large peak rise of ytterbium is due to the fact that shortly after the peak of lutetium, a shift to a high concentration of HIBA occurs, so that ytterbium can be obtained in a reasonable time and in an acceptable volume.

The chelating agent HIBA still contained in the eluate of the column S1 in this example was protonated by the addition of acid and was therefore presentAnd (4) inactivating. In that¹⁷⁷After Lu is collected, ytterbium is eluted from the first and second columns by using higher concentration HIBA and collected separately for recovery purposes.

The eluate of S1 may be flowed over the second pre-column system VS2 by adding acid to F2. In this example, the effluent was applied to the front-end column system VS2 as the third column by nitrogen pressure while still collecting additional effluent. During this process, it was required to add acid to flask F2 either at regular intervals or continuously. During loading, the column material of system VS2 was likewise converted to its H⁺Form (a). In order to remove unwanted H⁺Conversion of form to NH preferred for separation₄ ⁺Form with NH₄The VS2 system was washed with Cl and then with water. The front-end column system VS2 was then connected to the separation column S2 as a fourth column.

Additional separations were performed at moderate flow rates (1-10 ml/min) by HPLC pump P2. For this purpose, the gradient of water and HIBA optimized for separation in the VS2/S2 system was set as described above, while separation was performed by the pre-column system VS2 and the separation column S2.

The separation is monitored by a dose rate sensor. Upon elution from column S2¹⁷⁷Lu, the eluate was collected in a collection flask F3. The chelating agent HIBA still contained in the eluate is protonated and thus deactivated by the addition of acid. In that¹⁷⁷After Lu is collected, ytterbium is eluted from columns VS2 and S2 by using higher concentration of HIBA and collected separately for recovery purposes.

Fig. 3 shows the part of the column chromatography on column S2, where the dose rate is again plotted against the retention time in minutes. Similar to fig. 2, the ytterbium peak in fig. 3 (now only very small) only appears shortly after the lutetium peak (retention time about 135 minutes), because shortly after the lutetium peak (about 115 minutes), a shift to a high concentration of HIBA occurs. In addition, ytterbium in the separation process is only present after a few hours, which can unduly delay the process, of course for ytterbium recovery, especially¹⁷⁶Yb is useful.

The eluate of column S2 was loaded from collection flask F3 into final column S3 as a fifth column. For this purpose, while still collecting, the effluent was applied to column S3 by nitrogen pressure from collection flask F3. In the process, it was necessary to add acid to flask F3 at regular intervals. After stopping the loading of the final separation column S3, the column released HIBA by washing with dilute acid. Further separation of trace amounts of other metals and impurities, respectively, can be achieved by selectively washing the column S3 with different concentrations of acid.

After final purification of column S3,¹⁷⁷lu is eluted via a high concentration of acid into the evaporation unit 2. The acid is removed by evaporation. This step also serves to sterilize the final product.

¹⁷⁷Lun.c.a can now be absorbed into the desired solvent at the required concentration. Produced after final determination of the activity obtained and quality checks¹⁷⁷Lu is injected into vial 3 according to customer requirements.

In general, the carrier-free addition obtained by the process of the invention¹⁷⁷The Lu compound is characterized by showing a peak at only 177 atomic mass in the SF-ICP mass spectrum, and c.a.¹⁷⁷Lu shows three major peaks mainly at atomic weight units of 175, 176 and 177. This difference is shown in the mass spectrum of fig. 4. The ordinate represents the isotope distribution with a relative frequency range of 0 to 12. The abscissa in fig. 4 represents the atomic weight. The mass spectrometry used was sector field mass spectrometry with inductively coupled plasma [ sector field inductively coupled plasma-mass spectrometry, SF-ICP-MS]。

Claims (12)

1. From being irradiated by thermal neutrons¹⁷⁶High purity of Yb compounds for the production of essentially carrier-free additives for pharmaceutical purposes¹⁷⁷Method for producing Lu compounds, mainly containing Lu compounds in a mass ratio of approximately 1:10²To 1:10¹⁰Is/are as follows¹⁷⁷Lu and¹⁷⁶the neutron radiation end product of a mixture of Yb is used as a substrate, wherein the water-insoluble substrate is converted into a soluble form, and wherein the method comprises the steps of:

a) by dissolving in mineral acid and containing the same in a mass ratio of about 1:10²To 1:10¹⁰Is/are as follows¹⁷⁷Lu and¹⁷⁶a substrate of Yb loaded with a first column (VS1) packed with a cation exchange material; exchanging protons of the cation exchange material for ammonium ions, wherein NH is used₄A Cl solution; and washing the cation exchange material of the first column (VS1) with water;

b) connecting the outlet of the first column (VS1) with the inlet of a second column (S1) also filled with cation exchange material;

c) a gradient of water and chelating agent was applied from 100% H at the inlet of the first column (VS1)₂O start to 0.2M chelator, eluting from the first column (VS1) and the second column (S1)¹⁷⁷A Lu compound, said chelator selected from α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA and ammonium ions;

d) measuring the radiation dose at the exit of the second column (S1) to identify¹⁷⁷Elution of the Lu compound; the first from the outlet of the second column (S1)¹⁷⁷Collecting the Lu eluate in a container (F2); and protonating the chelating agent for use with¹⁷⁷Inactivation of the chelating agent of the Lu ion-forming complex;

e) by continuously conveying the acidity of step d)¹⁷⁷The inlet of the Lu eluate to the final column (S3), loading the final column (S3) filled with cation exchange material; washing the chelating agent with dilute mineral acid at a concentration of less than about 0.1M; by washing the cation exchange material of the final column (S3) with various concentrations of mineral acid ranging from about 0.1 to 2.5M¹⁷⁷Removing trace amounts of other metal ions from the Lu solution;

f) eluting from the final column (S3) by a high concentration of about 3 to 12M mineral acid¹⁷⁷Lu ion; will have high purity¹⁷⁷The Lu eluate is collected in an evaporation unit and the mineral acid is removed by evaporation.

2. Method according to claim 1, characterized in that between steps d) and f) the following steps are additionally carried out:

d.1) continuous conveying of the acidity of step d)¹⁷⁷Lu eluate to the inlet of a third column (VS2) packed with cation exchange material, due to the acidic loading¹⁷⁷The eluate of Lu is purified by washing,the cation exchange material is present in protonated form; exchanging protons of the cation exchange material for ammonium ions, wherein NH is used₄A Cl solution; and washing the cation exchange material of the third column (VS2) with water;

d.2) connecting the outlet of the third column (VS2) with the inlet of a fourth column (S2) filled with cation exchange material;

d.3) applying a gradient of water and chelating agent from 100% H at the inlet of the third column (VS2)₂O to 0.2M chelating agent, eluting from the third (VS2) and fourth (S2) columns¹⁷⁷A Lu compound, the chelating agent selected from the group consisting of α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA and ammonium ion;

d.4) determining the radiation dose at the exit of the fourth column (S2) for identification¹⁷⁷Elution of the Lu compound; passing the second from the outlet of the fourth column (S2)¹⁷⁷Collecting the Lu eluate in a container (F3); and protonating the chelating agent for use with¹⁷⁷The chelating agent of the Lu ion forming complex is deactivated.

3. The process according to claim 1 or 2, characterized in that in steps d) and d.4) the elution is carried out¹⁷⁷After the Lu compound, the first (VS1) and second (S1) and third (VS2) and fourth (S2) columns were washed with a higher concentration of chelating agent to elute Yb ions from the cation exchange material, and the obtained solution mainly comprised of Yb ions¹⁷⁶The Yb eluate of Yb ions was collected separately for the following purposes: reuse of the Yb eluate as a manufacturing¹⁷⁷Base material of Lu.

4. The process according to claim 1, characterized by HNO₃HCl, HF or H₂SO₄Or an organic acid, in particular acetic acid, is used as acid.

5. The method according to claim 1, characterized by using 1M to 12M HNO₃、H₂SO₄Or other oxidizing acids to render them water insoluble¹⁷⁶The Yb oxide is converted to a water soluble form.

6. The process according to claim 1, characterized in that HNO is used in an acid concentration of 0.01M to 2M₃HCl or other inorganic and/or organic acids.

7. The method according to claim 1, characterized in that the cation exchange material is selected from the group consisting of: macroporous cation exchange resins and gel-like cation exchange resins based on organic polymers, in particular those based on polystyrene; and silicate-based cation exchange resins.

8. The method of claim 1, wherein gram-sized substrates are used and milligram-sized substrates are produced¹⁷⁷Lu。

9. The method according to claim 1, characterized in that¹⁷⁷Number TBq of Lu and about 3.9TBq of Lu per mg of lutetium¹⁷⁷Specific activity of Lu.

10. From being irradiated by thermal neutrons¹⁷⁶Production of substantially carrier-free added high purity in Yb compounds for therapeutic and/or diagnostic purposes¹⁷⁷Method for producing Lu compounds, mainly containing Lu compounds in a mass ratio of approximately 1:10²To 1:10¹⁰Is/are as follows¹⁷⁷Lu and¹⁷⁶the neutron radiation end product of a mixture of Yb is used as a substrate, wherein the water-insoluble substrate is converted into a soluble form, and wherein the method comprises the steps of:

a) by dissolving in mineral acid and containing the same in a mass ratio of about 1:10²To 1:10¹⁰Is/are as follows¹⁷⁷Lu and¹⁷⁶a substrate of Yb loaded with a first column (VS1) packed with a cation exchange material; exchanging protons of the cation exchange material for ammonium ions, wherein NH is used₄A Cl solution; and useWater washing the cation exchange material of the first column (VS 1);

b) connecting the outlet of the first column (VS1) with the inlet of a second column (S1) also filled with cation exchange material;

c) a gradient of water and chelating agent was applied from 100% H at the inlet of the first column (VS1)₂A chelating agent selected from the group consisting of α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ions, starting with O to 0.2M;

d) measuring the radiation dose at the exit of the second column (S1) to identify¹⁷⁷Elution of the Lu compound; the first from the outlet of the second column (S1)¹⁷⁷Collecting the Lu eluate in a container (F2); and protonating the chelating agent for use with¹⁷⁷Inactivation of the chelating agent of the Lu ion-forming complex;

e) continuous conveying of the acidity of step d)¹⁷⁷Lu eluate to the inlet of a third column (VS2) packed with cation exchange material, due to the acidic loading¹⁷⁷Lu eluate, the cation exchange material being present in protonated form; exchanging protons of the cation exchange material for ammonium ions, wherein NH is used₄A Cl solution; and washing the cation exchange material of the third column (VS2) with water;

f) connecting the outlet of the third column (VS2) with the inlet of a fourth column (S2) filled with a cation exchange material;

g) a gradient of water and chelating agent was applied from 100% H at the inlet of the third column (VS2)₂A chelating agent selected from the group consisting of α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ions, starting with O to 0.2M;

h) measuring the radiation dose at the outlet of the fourth column (S2) for identification¹⁷⁷Elution of the Lu compound; passing the second from the outlet of the fourth column (S2)¹⁷⁷Collecting the Lu eluate in a container (F3); and protonating the chelating agent for use with¹⁷⁷Inactivation of the chelating agent of the Lu ion-forming complex;

i) by continuously conveying the acidity of step h)¹⁷⁷Lu eluate to the inlet of a fifth column (S3), loading the fifth column (S3) packed with a cation exchange material; with dilute mineral acidsWashing out the chelating agent; by washing the cation exchange material of the fifth column (S3) with various concentrations of mineral acid ranging from about 0.01 to 2.5M¹⁷⁷Removing trace amounts of other metal ions from the Lu solution;

j) eluting from the fifth column with about 3M to about 12M concentrated mineral acid¹⁷⁷Lu ion; will have high purity¹⁷⁷The Lu eluate is collected in an evaporation unit and the mineral acid is removed by evaporation.

11. The process according to claim 10, characterized in that it is carried out in a class C hot chamber according to EU-GMP regulations.

12. Gram order of cation exchange chromatography column¹⁷⁶Manufacture of milligram-grade high purity unsupported additions in Yb substrates¹⁷⁷Use of a Lu compound, wherein a cation exchange resin is used as stationary phase and a chelating agent is used as mobile phase, wherein a column is packed with cation exchange material and NH is used₄The Cl solution exchanges protons of the cation exchange material for ammonium ions;

a gradient of water and chelating agent was applied at the inlet of the column from 100% H₂A chelator from O onset to 0.2M, wherein the chelator is selected from α -Hydroxyisobutyrate (HIBA), citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ions;

determining radiation dose at column exit to identify¹⁷⁷Elution of the Lu compound.