EA040260B1 - PHARMACEUTICAL PREPARATION FOR USE IN ENDORADIONUCLIDE THERAPY - Google Patents

Description

State of the art

The invention relates to the field of endoradionuclide therapy, in particular α-endoradionuclide therapy. More specifically, the invention relates to the safety and efficacy of preparations for use in endoradionuclide therapy, such preparations and methods for their preparation, processing and safe storage.

The basic principle of endoradionuclide therapy is the selective destruction of unwanted cell types, for example, for cancer therapy. Radioactive decay releases a significant amount of energy, which is carried by high-energy particles and/or electromagnetic radiation. The released energy causes cytotoxic cell damage, resulting in direct or indirect cell death. Obviously, to be effective in treating disease, radiation must be selectively targeted to diseased tissue, such that this energy and cell damage will primarily remove unwanted tumor cells or cells that support tumor growth.

Some β-particle emitters have long been considered effective in treating cancer. Recently, α-particle emitters have begun to be used in anticancer drugs. α-particle emitters have several differences from β-particle emitters: for example, they have higher energy and shorter range in tissues. The radiation range of typical α-particle emitters in a physiological environment, as a rule, is less than 100 μm, i.e. equivalent to only a few cell diameters. This relatively short range makes α-particle emitters particularly suitable for the treatment of tumors, including micrometastases, since with effective targeting and containment, relatively little of the emitted energy misses the target cells, thus minimizing damage to surrounding healthy tissue. In contrast, the range of β-particles in water is 1 mm or more.

The energy of α-particle emission is high compared to the energy of β-particles, γ-rays and X-rays, which is usually 5-8 MeV or 5-10 times higher than that of β-particle emission and at least 20 times higher than with γ-radiation. Providing a very large amount of energy over a very short distance produces α-radiation with exceptionally high linear energy transfer (LET) compared to β- or γ-radiation. This explains the exceptional cytotoxicity of α-emitting radionuclides, as well as strict requirements for the level of control and study of the distribution of radiopharmaceuticals, which are necessary to avoid unacceptable side effects due to irradiation of healthy tissue.

Thus, despite the strong effect, the delivery of α-emitting radionuclides to the tumor with little or no uptake in healthy tissues is important. This can be achieved by analogy with the principle demonstrated in the delivery of the β-emitting radionuclide yttrium-90 (Y-90) using a monoclonal antibody conjugated to a chelating DTPA molecule as a carrier, i.e. the clinical radiopharmaceutical Zevalin® (Goldsmith, SJ, Semin. Nucl. Med. 40: 122-35. Radioimmunotherapy of lymphoma: Bexxar and Zevalin). Thus, a complex of radionuclide and carrier-chelator conjugate is introduced. In addition to full-length antibodies of various origins, other types of protein carriers have been described, including antibody fragments (Adams et al., A single treatment of yttrium-90-labeled CHX-A-C6.5 diabody inhibits the growth of established human tumor xenografts in immunodeficient mice. Cancer Res. 64: 6200-8, 2004), domain antibodies (Tijink et al., Improved tumor targeting of anti-epidermal growth factor receptor Nanobodies through albumin binding: taking advantage of modular Nanobody technology. Mol. Cancer Ther. 7: 2288 - 97, 2008), lipocalins (Kim et al., High-affinity recognition of lanthanide(III) chelate complexes by a reprogrammed human lipocalin 2. J. Am. Chem. Soc. 131: 3565 - 76, 2009), mimetic molecules antibodies from Affibody (Tolmachev et al., Radionuclide therapy of HER2positive microxenografts using a ¹⁷⁷ Lu-labeled HER2-specific Affibody molecule. Cancer Res. 15:2772-83, 2007) and peptides (Miederer et al., Preclinical evaluation of the alpha particle generator nuclide ^{22 5} Ac for somatostatin receptor radiotherapy of neuroendocrine tumors. Clin. Cancer Res. 14:3555-61, 2008).

The decay or destruction of many pharmaceutically relevant α particle emitters results in the formation of progeny nuclides that can also be destroyed to release α radiation. The destruction of daughter nuclides can lead to the formation of third types of nuclides, which can also be emitters of α-particles, which leads to a continuous chain of radioactive decay - a decay chain. Thus, a pharmaceutical preparation of a pharmaceutically relevant α particle emitter often also contains degradation products that are themselves α particle emitters. In such a situation, the preparation contains a mixture of radionuclides, the composition of which depends both on the preparation time and on the half-life of the various radionuclides in the decay chain.

The very high energy of the α-particle, combined with its significant mass, results in the transfer of significant momentum to the radiated particle after nuclear decay. As a result, when the α particle is released, an equal but opposite momentum is transferred to the remaining daughter nucleus, leading to the recoil of the nucleus. This recoil is powerful enough to destroy most chemical bonds and to displace the newly formed daughter nuclide from the chelate complex in which the original nuclide was located during destruction. This is of great importance if the daughter nucleus itself is a source of α-radiation or is part of a continuous chain of radioactive decay.

Because of the aforementioned recoil effects and the change in chemical properties after radioactive decay, the daughter nuclides thus formed from the radioactive decay of the initially included radionuclide may not be complexed with the chelator. Thus, in contrast to the initial nuclide, the daughter nuclides and subsequent products in the decay chain may not be attached to the carrier. Thus, storage of an α-emitting radioactive pharmaceutical typically results in the accumulation of ingrowth free daughter nuclides and downstream radionuclides in the decay chain that have lost their ability to effectively bind or chelate. Unbound radioisotopes are not controlled by the targeting mechanisms included in the desired preparation, and thus it is desirable to remove free daughter nuclides before dosing to a patient.

Because the radioisotope thorium-227 is generated and purified in a dedicated manufacturing facility, a certain storage period is inevitably required between formation, transport, complexation, and dose administration, and it is desirable that the pharmaceutical formulation be as free of progeny as possible. A significant problem in connection with the above method is the introduction of a reproducible target α radionuclide composition that does not contain a variable amount of non-target α radionuclides (eg, free daughter nuclides) relative to the target amount. It is also desirable to reduce the exposure of organic components, such as binding/targeting components and/or ligands, to ionizing α-radiation. Removal of free radioisotopes from solution helps to reduce the radiolysis of such components and thus helps to maintain the quality of the pharmaceutical product or stock solution.

Although the decay of the desired nuclide during storage and transport can be calculated and corrected for, this does not avoid the formation of non-target progeny products that make the composition more toxic and/or shorten the safe storage period and/or adversely change the therapeutic window. In addition, in this way, preference is given to compositions that, if possible, do not include progeny nuclides, and the organization of the production process of dosed medicaments, which would guarantee the safety of the composition of the dose administered by injection.

The events resulting from the decay of thorium-227 can be seen as an illustration of the problem.

With a half-life of approximately 18.7 days, thorium-227 decays into radium-223 after the release of α-particles. Radium-223, in turn, has a half-life of approximately 11.4 days and decays into radon-219 to form polonium-215, which forms lead-211. Each of these steps produces α-radiation, and the half-lives of radon-219 and polonium-215 are less than 4 s and less than 2 ms, respectively. The end result is that the radioactivity in a freshly prepared solution of, for example, chelated thorium-227 increases in the first 19 days and then begins to decrease. Obviously, the amount of thorium-227 available for tumor targeting is constantly decreasing, and thus the proportion of total radioactivity that is due to thorium-227 decreases during these 19 days, when an equilibrium situation is reached. If progeny nuclides could be intentionally removed using a simple procedure, only the amount of thorium-227 would have to be considered (e.g., in complex with the carrier biomolecule), and the therapeutic window—the relationship between therapeutic effect and adverse effect—was not related to storage time before removal. daughter isotopes. This process may be continuous during storage of the product, or may occur shortly before administration, such as during formulation and complexation providing the drug product.

Thus, there is a continued significant need for improved radiotherapy compositions (particularly for α-emitting radionuclides) and procedures for preparing an injectable solution whose biological effects can be determined in a reproducible manner, without the need to take into account ingrown radionuclides generated in the radioactive decay chain. In addition, there is a need for radiotherapy methods and kits that allow the final radioactive composition to be easily manufactured under sterile conditions immediately prior to administration to a patient. In addition, in terms of producing high quality commercial products that meet the rigorous standards of Modern Good Manufacturing Practice (cGMP) principles, it is desirable that the manufacturing process be amenable to automation with minimal manual intervention during dose preparation.

The present invention may relate to compositions, methods and procedures for removing cationic progeny nuclides from a radiopharmaceutical preparation containing the parent radionuclide, which may be provided in the form of a solution or may be stably chelated into a form comprising a ligand and a targeting moiety, i.e. the parent radionuclide is or can be complexed with a ligand that is itself conjugated to a targeting moiety (such as an antibody). In particular, the present inventors have surprisingly found that progeny radionuclides can be safely and reliably captured on various selective binders continuously during storage of the radioisotope and/or shortly before administration of the radioisotope in the form of a radiopharmaceutical. In particular, the radionuclides captured by the selective binders are α-emitting radionuclides or generators for α-emitting radionuclides, which are typically formed during the decay of the original α-emitting radionuclide and/or by further decay of resulting daughter nuclides. A typical decay chain for ²²⁷ Th is described by the authors, and the isotopes indicated in this chain form the preferred daughter isotopes, which in various aspects of the present invention can be removed and/or captured. Ready therapeutic compositions resulting from the application of the invention are suitable for use in the treatment of cancer and non-cancer diseases.

Alternatively, a composition can be provided that allows radioactive progeny nuclides to be removed during storage and/or just prior to administration (eg, injection) in which ingrown radioactive decay products have been removed. As a result, the concomitant administration of progeny nuclides is minimized and thus the radiation dose and radiation damage to normal and non-target tissues is minimized.

Thus, only the concentration and half-life of the parent radionuclide and progeny produced in vivo should be taken into account when calculating the radioactive dose to the patient. Most importantly, this leads to a reproducible situation regarding the relationship between efficacy and adverse effects. Thus, the available therapeutic window does not change during the storage of the pharmaceutical product.

In other words, when applying the invention, the ratio between the desired antitumor effect and the adverse effect can be directly related to the measured concentration of the primary nuclide and becomes independent of the shelf life of the pharmaceutical product. In situations in which the concentration of the primary α-emitting radionuclide can be determined by measuring one or more parallel γ-particle emissions sufficiently separated from the γ-particles from daughter emissions, this can be done using standard equipment in radiopharmacology. In fact, if the drug product is pure in relation to the parent nuclide, the appropriate dosage of the pharmaceutical product depends only on the time after manufacture and can be tabulated. In principle, there is no need for further measurements in the clinic, and the handling of the corresponding radiopharmaceutical can be similar to that of other toxic pharmaceuticals (although such a procedure would be contrary to current practice, which is based on the fact that radioactivity can be easily measured). Enabling this new and simplified procedure for the clinical use of targeted α-particle emitting radiotherapy

- 3 040260 funds is an important aspect of the invention.

In yet another embodiment, the invention relates to providing a kit for a pharmaceutical formulation. Kits are typically supplied to a hospital pharmacy or radiopharmaceutical center and may be prepared for administration shortly (eg, less than 6 hours) or immediately (eg, less than 1 hour) prior to administration. A significant advantage is the ability to perform purification of the desired α-emitting radionuclide during the preparation of the pharmaceutical preparation for administration. Another advantage is that the cleanup can be carried out without unnecessary effort and complex operations, since the handling of radioactive materials is desirable to be kept to a minimum.

The kit according to the invention can be provided in the form of a device, for example a cassette laboratory, which is accompanied by test tubes or vials containing various reagents, as well as a syringe containing a finished dosage form of a pharmaceutical preparation intended for injection. The device performs operations that would otherwise have to be performed manually.

The present inventors have found that certain selective binders, particularly in the form of solids or gels or immobilized thereon, retain cationic progeny nuclides to a high degree after decay of the parent nuclide. The selectivity of these materials allows for the retention of progeny isotopes, but allows complexes of the parent radioisotopes (for example, a thorium isotope such as ^227Th complexed with a ligand optionally attached to the biomolecule) to pass through the filter unhindered or remain in solution while the progeny are retained. This provides a significant advantage in the manufacture and delivery of high quality radiopharmaceuticals that can be prepared directly or shortly before administration, but delivered with a relatively low level of contamination from unbound progeny radionuclides.

Brief description of the invention

In a first aspect, the invention thus provides a pharmaceutical process for producing a complex α-particle emitting radionuclide (optionally in the form of a biomolecule conjugate). Preferably, the above process includes as a key component a selective binder (such as a solid phase resin filter) capable of selectively absorbing, binding, complexing, or otherwise removing unbound child nuclides formed during the decay of thorium-227 from solution. They can be direct daughter nuclides or subsequent nuclides in the radioactive decay chain. In particular, ²²³ Ra and its well-known decay products (including ²¹⁹ Rn, ²¹⁵ At, ²¹⁵ Po, ²¹¹ Po, ²¹¹ Bi, ²¹¹ Pb, ²⁰⁷ Pb and ²⁰⁷ T1) are typical progeny to be removed, as are any of those shown. in this description in the thorium decay chain.

A key aspect of the present invention is thus a method of forming a purified solution of at least one complex α-particle emitting radionuclide, the above method comprising contacting a solution comprising the aforementioned at least one α-particle emitting radionuclide complex and at least one daughter nuclide with at least one a selective binder for the aforementioned at least one daughter nuclide and then separating the aforementioned solution of at least one α particle emitting radionuclide complex from the aforementioned at least one selective binder.

In all aspects of the present invention, the daughter nuclides are typically unbound. This may be a result of the kinetic recoil that is created after α-decay and/or as a result of differences in complexation properties between parent and daughter nuclide. All radionuclides used according to the present invention, as a rule, are heavy metal radionuclides having, for example, an atomic mass of more than 150 amu. (for example, from 210 to 230). Typical α-emitting heavy metal radionuclides include At, ²¹² Bi, ²²³ Ra, ²²⁴ Ra, ²²⁵ Ac and ²²⁷ Th. Preferred α-emitting (raw) radionuclides include α-emitting thorium radionuclides such as ²²⁷ Th, which is most preferred.

The inventors have surprisingly found that suitable selective binder materials (described by the inventors, for example, solid phase resin materials) are highly effective in scavenging unwanted unbound progeny ions in the presence of bound thorium, optionally conjugated to target components (such as biomolecules). Thus, in a second aspect, the present invention provides a method for providing an injection solution comprising at least one bound α-particle emitting radionuclide substantially free of progeny nuclides, the above method comprising contacting a sample with a suitable selective binder, preferably this contact taking place by performing a simple purification/filtration step, resulting in highly purified, radiochemically purified pharmaceuticals having a high level of the desired α-emitting (eg, thorium) complex (optionally conjugated to a targeting moiety). As a rule, immediately after separation of the labeled thorium complex (and, optionally, the conjugate), sterile filtration is performed. It is particularly useful as a final step before administration.

According to the present invention, the α-emitting radionuclide that is required for administration (parent radionuclide) is described hereinafter and must be bound or in the form of a complex. The general meaning of these terms is that the α-emitting radionuclide is provided in the form of a coordination complex comprising the heavy metal radionuclide cation and at least its associated ligand. Suitable ligands, including those described by the authors, are well known to those skilled in the art.

Since pharmaceutical preparations can be created from the solutions of the present invention, the invention provides such pharmaceutical preparations. They include a solution of the α-emitting radionuclide and contain virtually no daughter nuclides, as indicated by the authors. In a pharmaceutical formulation of the invention, the α-emitting radionuclide must be bound to at least one ligand, and the ligand must be conjugated to a targeting (specifically binding) moiety as described by the inventors. Solutions according to the invention may be provided directly in the administration device (such as a syringe, cartridge or syringe barrel) in a ready-to-administer form, the invention making it possible to purify the solution to a pharmaceutical preparation during administration and even through the administration process (for example, by administration through suitable specific binder in the form of a syringe filter). Thus, devices according to the invention may be administration devices such as syringes. Thus, the invention in another aspect provides an administration device comprising a solution as described by the authors. Such a device may further include, for example, a filter, such as a sterile filter. Syringe filters are suitable for syringes and other similar devices.

Thus, the invention provides an administration device comprising a solution of at least one bound α particle emitting radionuclide and at least one daughter nuclide, said device also comprising a filter containing at least one selective binder for said daughter nuclide. Other devices according to the invention, which also include a solution of an α-particle emitting radionuclide, a ligand, a targeting component and a selective binder, are provided in the form of (preferably disposable) cartridges, cassettes, rotors, vials, ampoules, etc., which can be used in according to the methods according to the invention, by performing manual steps and/or automated procedures in an automatic device.

Another key aspect of the present invention relates to a kit with which a pharmaceutical preparation can be created. Thus, in yet another aspect, the invention provides a kit for making a pharmaceutical preparation of at least one α-particle emitting radioisotope, said kit comprising:

i) a solution of the aforementioned at least one α-emitting radioisotope and at least one daughter isotope;

ii) at least one ligand;

ii) a specific binder;

iii) at least one selective binder for the aforementioned at least one daughter isotope.

Wherein, said α-emitting radioisotope is or may be bound by the aforementioned ligand, which is or may be conjugated with the aforementioned specific binder.

In one embodiment, the α-emitting radionuclide binds to a ligand but cannot be conjugated to a specific binding (targeting) moiety. Alternatively, the ligand may be stably conjugated to the targeting moiety and kept in a vessel separate from the radioisotope. Keeping the organic molecules of the complex (ligand and/or targeting component) separate from the α-particle emitter reduces radiation damage (eg, oxidation) to the organic material due to exposure to α-radiation during storage.

In one embodiment, the kit may be provided as two vials. Such a kit includes a vial with a radioisotope (eg, thorium-227) and a second vial containing a biomolecule conjugate buffer solution appropriately conjugated to a ligand (chelate) that binds to thorium-227. Immediately before preparation of the medicinal product, the contents of the vial with thorium-227 are mixed with a solution of the biomolecule conjugate.

Capture of (unbound) radionuclides, in particular free daughter radionuclides, from a solution containing at least one bound α-emitting radioisotope (such as the parent radioisotope) and at least one organic component (such as a complexing agent

- 5 040260 and / or targeting agent) serves to reduce the impact on the organic component of ionizing radiation from further decay of free radionuclides (for example, daughters). In all relevant aspects of the present invention, the daughter radionuclide (same as the radioisotope) is usually free in solution. This means that the radionuclide is provided in the form of a dissolved ion and is not (or is not substantially) complexed or bound by ligands in solution. The daughter radionuclide can obviously bind to a specific binder, but this usually does not occur in solution (as described by the authors). In the context of this description, the term daughter radionuclide has a common meaning among experts, in the sense that such nuclides are formed directly or indirectly from the decay of another radioisotope. In this case, at least one daughter radionuclide present in solutions that is referred to in any and every aspect of the invention is a direct (first generation) or indirect (second, third or subsequent generation) decay product of a radionuclide present in an α-particle emitting radionuclide complex . Preferably, at a minimum, the decay product of the first generation radionuclide included in the α-particle emitting radionuclide complex must be present in such solutions and must be bound by a selective binder.

Detailed description of the invention

As described above, the degree of presence of ingrown progeny radionuclides in the thorium vial during complexation depends on the time of storage and transport. However, the daughter nuclides do not affect the complex formation of the α-radiating radionuclide (thorium-227) with the conjugate of the biomolecule, since the chelate is chosen in such a way that the desired radionuclide (for example, thorium) has a significantly higher affinity for the chelate compared to the daughter ones. In a second, batch process, the daughter nuclides are separated from the now thorium labeled biomolecule by filtration through a specific binder. It may be provided in the form of a solid phase filter cartridge.

This process of separating the alpha particle emitting material from the organic ligand and/or targeting component has the additional benefit of reducing the rate of radiolysis (eg, biomolecule carrier and/or chelating component) of the radiopharmaceutical and can be applied to all aspects of the invention. Because the radioactive product is produced closer to the patient's bedside than other currently used strategies, the material must have a higher degree of radiochemical and/or organic material purity (ligand and/or targeting components). This offers advantages in terms of compliance with shelf life requirements.

Injectable solutions which are or can be formed using the methods of the invention are very suitable for use in therapy, in particular for use in the treatment of hyperplastic diseases or tumors. Pharmaceutical preparations which are or can be formed in various ways according to the invention represent other aspects of the present invention.

In the context of this description, the term pharmaceutical preparation means a radionuclide preparation with pharmaceutically acceptable carriers, excipients and/or diluents. However, the pharmaceutical preparation need not be in the form of its final administration. For example, a pharmaceutical preparation may require the addition of at least one more ingredient prior to administration and/or may require final preparation steps such as sterile filtration. The other component may be, for example, a buffer solution used to make the final solution acceptable for in vivo injection. In the context of the present invention, the pharmaceutical preparation may contain a significant level of unbound radionuclides as a result of the radioactive decay chain of the desired radionuclide complex, which are preferably subject to removal to a large extent by the method of the present invention prior to administration. Such a method may include periodic removal (eg, selective binding, chelation, complexation or absorption) of such unbound daughter radionuclides during a significant part of the period of storage of the drug, or may be performed at the final stage, immediately before administration.

In contrast to a pharmaceutical product, the terms injectable solution or finished composition used by the authors mean a drug that is ready for administration. Such a composition also includes a preparation of bound radionuclide with pharmaceutically acceptable carriers, excipients and/or diluents, but must be sterile, have proper tonicity, and must not contain unacceptable levels of unbound radioactive decay products. These levels are discussed in more detail below. Obviously, the injection solution should not include any biopolymer component, although such a biopolymer would preferably be used in the preparation of the solution discussed herein.

Injectable solutions, which are formed or can be formed by any of the methods according to the present invention, constitute another aspect of the invention.

- 6 040260

The invention provides a simple method or process for purifying and preparing a sterile finished composition of a radioactive preparation ready for administration using specific binders in the form of absorbent materials and/or filters to absorb unwanted radioactive decay products, resulting in a rapid separation of unwanted nuclides during storage and /or immediately prior to administration to the patient. Separation may be followed by sterile filtration, which is performed when drawing up the finished composition into a syringe, which is then used for administration to a patient, or may even be performed as part of the administration.

In the described implementation, the invention provides a simple kit (as described by the authors) for cleaning and finished composition of a radioactive drug for use in therapy. Kits according to the invention may include, for example, a vessel with thorium (such as a vial, syringe or syringe barrel) containing a solution of a radioactive salt of thorium (for example, ²²⁷ Th salts), a vessel (for example, a vial) with a pharmaceutical solution (for example, a ligand conjugated with a targeting component such as an antibody or receptor), a filter containing at least one specific binder for the child(s) of the nuclide(s), optionally a sterile filter and a syringe. Kit components may be separate or may be combined into a single unit or flow cell to form a closed system, thus reducing the chance of introducing unwanted by-products during manufacture. Avoidance of steps during which radiochemical contamination can occur is a distinct advantage of kits including components wholly or partly sealed together so that the material remains within the kit for as many process steps as possible.

The invention provides for the use of a procedure for preparing a finished composition for injection, for example using components provided in the form of a kit. The procedure according to any of the methods and/or uses according to the invention may include an incubation step in which the solution or pharmaceutical preparation is mixed, for example by gentle agitation to allow optimal formation of the thorium complex with the biomolecule-chelate conjugate, followed by filtration to remove unwanted progeny. nuclides.

One example of a procedure for generating an α-radionuclide injection solution includes the steps of:

a) combining a first solution comprising a dissolved salt of an α-emitting thorium isotope and at least one radium isotope with a second solution comprising at least one chelator conjugated to at least one targeting antibody component;

b) incubating the combined solutions at a suitable temperature between 0 and 50°C, preferably between 20 and 40°C, for a period allowing the formation of a complex between the aforementioned chelator and the aforementioned α-emitting isotope of thorium, which ensures the formation of a solution of at least one a bound α-radiating thorium isotope;

c) contacting said solution of at least one bonded thorium isotope emitting α-particle with at least one selective binder for at least one of said radium isotopes;

d) separating said solution of at least one bound α-particle emitting thorium isotope from said at least one selective binder.

According to the injection solution formation method, steps c) and d) represent a purification method that can be performed in accordance with any of the relevant embodiments of the invention, as described by the authors. In this embodiment, the nuclides, binders, ligands, and all relevant aspects are as described herein.

Pharmaceutical preparations according to the invention, together with purified solutions formed using the methods according to the invention, and injectable solutions formed using the methods according to the invention, preferably have a low concentration of unbound progeny metal ions. As a rule, for example, the concentration of a solution of daughter nuclides should preferably be no more than 10% of the total rate of radioactive decay per unit time (from solution), and the rest falls on the decay of the associated (for example, thorium) α-radionuclide. Preferably this value is not more than 5% of the total value, more preferably not more than 3%.

Optimally, the α-radionuclide conjugates of the present invention contain thorium-227, with the process being most efficient preferably at removing Ra. Other daughter isotopes may also be removed as described herein. In the pharmaceutical preparations of the invention and, accordingly, in the resulting injectable solutions, as well as in all aspects of the invention, the radionuclide is bound or may be bound by a suitable complexing/chelating entity (generally referred to herein as a ligand). Many suitable ligands are known for various suitable α particle emitting radionuclides, such as those based on DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10tetrucacetic acid) and other macrocyclic chelators, such as chelating hydroxyphthalic acid or hydroxyisophthalic acid. acid, as well as various variants of DTPA (di

- 7 040260 ethylenetriaminepentaacetic acid), or containing octadentate hydroxypyridinone chelators. Preferred examples are chelators comprising a hydroxypyridinone component, such as a 1,2-hydroxypyridinone component and/or a 3,2-hydroxypyridinone component. They are very well suited for use in combination with ²²⁷ Th. In one embodiment of the invention, the α-particle emitting radionuclide complex is the 3,2HOPO octadentate complex of the ^227Th ion.

In the pharmaceutical preparations of the invention and, accordingly, in the resulting solutions for injection and all other aspects of the invention, at least one bound α-particle emitting radionuclide is preferably conjugated or can be conjugated to at least one targeting component (also described here as a specific binder component). Many such components are well known to those skilled in the art, and any suitable targeting component may be used, alone or in combination. Suitable target components include poly- and oligopeptides, proteins, DNA and RNA fragments, aptamers, and the like. Preferred components include peptide and protein binders, such as avidin, streptavidin, a polyclonal or monoclonal antibody (including IgG and IgM type antibodies), or a mixture of proteins or protein fragments or constructs. Antibodies, antibody constructs, antibody fragments (eg, Fab fragments, single domain antibodies, single chain variable domain (scFv) fragments, etc.), constructs containing antibody fragments, or a mixture thereof are particularly preferred.

Antibodies, antibody constructs, antibody fragments (eg Fab fragments or any fragment including at least one antigen-binding site), fragment constructs (eg single chain antibodies) or a mixture thereof are particularly preferred. Suitable fragments include, in particular, Fab, F(ab')2, Fab' and/or scFv. Antibody constructs may refer to any antibody or fragment as defined in this specification.

In addition to the various components mentioned in this description, pharmaceutical preparations may contain any suitable pharmaceutically compatible components. In the case of radiopharmaceuticals, they should generally include at least one stabilizer. Radical scavengers such as ascorbate, p-ABA and/or citrate are particularly suitable. Serum albumin, such as BSA, is also a suitable additive, in particular for the protection of protein and/or peptide components such as antibodies and/or fragments thereof.

In accordance with the methods of use according to the present invention, the contact between the pharmaceutical solution and the selective binding agent (for example, a solid phase resin filter) can occur for an extended period of time (for example, at least 30 minutes, for example, at least one 1 hour or at least 1 day). In this embodiment, the selective binder may be present with the α-emitting radionuclide solution during storage. However, in an alternative embodiment, the aforementioned contract occurs quickly (for example, within less than 30 minutes, less than 10 minutes, or less than 5 minutes (for example, less than 1 minute or no more than 30 seconds). In such an embodiment, a selective binder such as typically provided in the form of a solid material or associated with a solid material (as described by the authors) and may be in the form of a separating column, pad or filter for the passage of the solution Such passage may be by gravity or by centrifugal force, may be caused by suction or most preferably caused by overpressure, for example, by applying pressure to the syringe barrel.In this case, the contact occurs when the solution is forced through the filter/pad/column.Although rapid separation is the most preferred method, in the alternative, the contact and filtration step can occur over longer periods time (eg. 3 to 20 min) to ensure maximum radiochemical purity.

In an alternative embodiment, the aforementioned contact/filtration takes place for no more than 30 seconds, preferably no more than 1 minute, followed by sterile filtration, and thus also forms a sterile solution suitable for injection. Accordingly, kits according to the invention may optionally and preferably additionally include a filter (eg, with a pore size of 0.45 µm or a pore size of approximately 0.22 µm). In all cases, preference is given to filtration through a filter with a pore size of not more than 0.45 µm, preferably not more than 0.22 µm. Such a filter may serve to retain the selective binder used in various aspects of the invention.

In various aspects of the present invention, the ligand component is typically conjugated or may be conjugated to at least one specific binding (targeting) component. Such conjugation may occur via a covalent bond (such as a carbon-carbon, amide, ester, ether or amine bond) or may occur through a strong non-covalent interaction such as the linkage of a pair of specifically binding components, eg biotin to avidin/streptavidin. Most preferably, the ligand is conjugated to the targeting moiety via a covalent bond, optionally via a linker (such as a Ci-Ci-alkyl group independently substituted at each end with an alcohol, acid, amine, amide, ester, or ester group) .

In all aspects of the present invention, the selective binder is typically provided in the form of a solid or gel, or is immobilized on a solid or gel matrix (such as a porous matrix or membrane). This provides ease of handling and separation, and also facilitates contact of the selective binder with the α-emitting radioisotope complex and subsequent separation. The solid material may be a material that retains its shape under light mechanical pressure, including pressure exerted by manual use of a syringe or pressure provided by an automatic device. Typically, the selective binder is provided in the form of or immobilized on the porous material so that the solution can pass through the pores of the material. Suitable matrices to support selective binders are discussed herein and are well known to those skilled in the art. These include metal oxides (eg silica, alumina, titanium dioxide), glass, metal, plastics, and the like. Selective binders may be immobilized on the surface of such matrices or may form their own porous matrices. Any of these materials can form the backbone in the form of membranes, resin beads, gel beads, self-assembling lipid structures (eg, liposomes), microparticles, nanoparticles, powders, crystals, and polymer structures, as appropriate. Obviously, several such structures can be used.

As a selective binder, at least one substance is chosen that has a higher affinity for the daughter(s) radionuclide(s) in solution compared to the α-particle emitting radionuclide complex. Suitable materials for selective binders include at least one of cation exchange resins, exclusion resins, zeolites, molecular sieves, alginates, liposomes, phosphonates, polyphosphonates, phospholipids, glycolipids, lipoproteins, oligosaccharides, ferritin, transferrin, phytic acid, and coprecipitants. . The most preferred selective binders include cation exchange resins, hydroxyapatite and zeolites.

These selective binders according to the present invention do not include a polysaccharide. These selective binders also do not include alginate. Said binder comprises, mainly consists of or consists of at least one inorganic material, for example at least one ceramic material. Inorganic resins (eg, inorganic ion exchange resins), metal oxides (such as silica, alumina, titanium dioxide, especially if they are porous, eg medium porosity), hydroxyapatite (including substituted hydroxyapatites), molecular sieves, and zeolites are the most preferred inorganic binders. materials.

Details of some materials suitable for use as selective binders are shown in Table 1 below. 1. The examples given in the description column represent the preferred choice of materials for use as selective binders according to the present invention.

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Table 1

Material Description Cation exchange resin An insoluble matrix, usually in the form of small granules, usually white or yellowish, made from an organic polymer base. The material has a highly developed pore structure, on the surface of which there are areas with easily captured and released ions. The capture of ions occurs only with the simultaneous release of other ions; thus, the process is called ion exchange. Exclusion / gel filtration resins Size exclusion chromatography (SEC) is a chromatographic method in which molecules in solution are separated by their size and, in some cases, by molecular weight. Molecular sieves A material containing minute pores of precise and uniform size that is used as an adsorbent Alginate (= alginic acid salts) linear copolymer with homopolymer blocks of (1-4)-linked β-Ο-mannuronate (M) and residues of its C-5 epimer a-L-guluronate (G), respectively, covalently linked to each other in different sequences or blocks Liposomes (sterically stabilized) artificially obtained vesicle, consisting mainly of a lipid bilayer. Liposomes are composed of naturally occurring phospholipids and may also contain mixed lipid chains with surfactant properties. The structure of liposomes may include surface ligands. (Poly-)phosphonate Phosphonates or phosphonic acids are organic compounds containing C-PO(OH)2 or C-PO(OR)2 groups (where R = alkyl, aryl). Phosphonic acids are known to be effective chelating agents. The incorporation of an amine group into the molecule to produce -NH2C-PO(OH)2 increases the metal-binding capacity of the phosphonate. Nanoparticles Nanoparticles are 100 to 1 nanometer in size. High surface area to volume ratio. Liposomes

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are an example of nanoparticles. Phospholipids A class of lipids that represent the main component of all cell membranes because they are able to form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule like choline. Glycolipids Lipids with an attached carbohydrate co-precipitation Drift with sediment of substances that are normally soluble under the applied conditions. Because the trace element is too dilute (sometimes less than one trillionth) to be deposited by conventional means, it is typically co-precipitated with a carrier, a substance having a similar crystal structure that may include the element of interest. Occurs by inclusion, adsorption or occlusion. Ferritin / apoferritin, transferrin / apotransferrin Ferritin is a globular protein complex that stores iron in a soluble and non-toxic form. Ferritin that does not combine with iron is called apoferritin. Transferrins are iron-binding plasma glycoproteins that regulate the level of free iron in biological fluids. Lipoproteins Biochemical structure containing proteins and lipids Cyclodextrins Cyclic oligosaccharides Phytic acid (phytate in case of salt form) Phosphorus compound with chelating action. It occurs naturally in plants as an insoluble calcium-magnesium salt and is the main source of phosphate in the diet, although its bioavailability remains controversial. Excessive intake of phytate is associated with a deficiency of elements such as calcium, iron and zinc. Surface modifications Agents with possible affinity for 223-Ra: Phytic acid Phospholipids Phosphonates Carriers: Liposomes Microparticles / Nanoparticles / Resins / Alginate / Polymer Granules / Cyclodextrins

In one aspect, the selective binder(s)(s) are provided(s) in the form of a column or filter. In this and other relevant embodiments, the contacting means is the flow of solution through or through the selective binder. Alternatively, when the selective binder is immobilized on the substrate, the flow may pass through or through the substrate. Preference is given to further passage through the sterile filtration membrane (as described by the authors).

The injectable solution obtained from the compositions or pharmaceutical preparations according to the invention are suitable for the treatment of a number of diseases and are particularly suitable for the treatment of diseases associated with unwanted cell proliferation, such as hyperplastic diseases and tumors. For example, metastatic and non-metastatic cancers such as small and non-small cell lung cancer, malignant melanoma, ovarian cancer, breast cancer, bone cancer, colon and rectal cancer, pancreatic cancer, bladder cancer, cervical cancer, sarcomas, lymphomas , leukemias, prostate tumors and liver tumors are all suitable targets. The subject of treatment may be a human or animal, in particular mammals, more specifically primates, canines, felines or rodents.

In yet another aspect, the invention encompasses a device, a kit, as described by the authors. Such kits include an α-particle emitting radioisotope, a ligand, a targeting component, and a selective binder for binding daughter nuclides. Typically, in use, the α-particle-emitting radionuclide is either present as an α-particle-emitting radionuclide complex, or is formed into such a complex by contact between a first solution of the aforementioned

- 11 040260 of that kit (comprising the α-emitting radionuclide and any daughter nuclides) and the second solution of the above kit (comprising the ligand conjugated to the targeting component). After conjugation, the α-particle emitting radionuclide complex is brought into contact with a selective binder. Contact may occur by any method described herein, but preference is given to passing a solution of the α-particle emitting radionuclide complex through a column, pad, filter, membrane, or plug of a selective binder material.

Kits according to the present invention typically include a selective binder in the form of a filter or column. The α-particle emitting radionuclide solution is usually present in the first container, however, this and all containers mentioned herein can be in the form of a vial, syringe, syringe barrel, cartridge, cassette, cup, ampoule, or any suitable container, as well as part of such a vessel, such as one well in a plate or one cavity in a multi-reagent cartridge or cassette. The first and second vessels, if present, may form a single device (for example, may be separate wells in a multi-component plate or cassette) and may be in fluid communication with each other, which is optionally provided by removing the cap, stopper or tap or removing the restriction , clamps, etc., to ensure the possibility of mixing solutions. Such mixing may be initiated manually or may be the result of manipulation in an automatic device.

One embodiment of kits according to the invention is provided in the form of cartridges for an automatic device, such as an automatic synthesizer. Such an automatic device allows the methods of the invention to be carried out with a minimum of manual intervention to ensure compliance with cGMP principles. Thus, a typical device includes an automated synthesizer such as a GEHC FastLab or TracerLab that contains or is loaded with a kit or device according to the present invention. An automatic device comprising a kit or device according to the invention thus constitutes another aspect of the invention. The kit according to the invention may be provided in the form of a device, a cartridge, a rotor, a reagent kit, and the like. for any of these or similar devices. The automated device can be used for a fully automated process involving complexing a radionuclide (e.g., thorium-227) with a ligand/biomolecule conjugate, removing child nuclides by filtration on a selective binder (e.g., solid phase resin), sterile filtration, and placement in a drug vial. product. Thus, various methods according to the invention can be performed using an automatic device, such as a device including a kit or device, as described by the authors.

In such an embodiment, the invention provides an insertion device. Such a device may contain a solution of a complex of the α-emitting radionuclide and daughter nuclides and includes a selective binder for the aforementioned daughter nuclides. In use, such an administration device can simultaneously remove progeny nuclides by passing the solution through or through a selective binder, and also deliver the resulting purified solution to the subject's body.

Injectable solutions which are and can be formed from the pharmaceutical compositions of the invention, and those which are formed by using kits according to the invention, obviously form another aspect of the invention. Such solutions may be, for example, an injectable solution comprising a solution of at least one bound emitting α particle radionuclide and at least one pharmaceutically acceptable carrier or diluent, wherein the solution concentration of any unbound ions resulting from the radioactive decay chain of the aforementioned at least one bound emitting α- particles of the radionuclide is not more than 10% of the concentration of the solution of the above at least one bound emitting α-particle radionuclide.

The invention is further explained with reference to the following non-limiting examples and drawing.

The drawing shows the formation of hydrogen peroxide by radiolysis of water in the presence or absence of a selective binder.

Example 1 Absorption of radium-223 on gravity columns using ceramic hydroxyapatite.

100 mg of ceramic hydroxyapatite were weighed and transferred to columns. HEPES buffer (5 mm, pH 8) was used to balance the column (3x1 ml). Then 1 ml of HEPES buffer was added to the column, which was left for a day before loading with 140 kBq of radium-223 in 1 ml. Absorption took place immediately after. The column was then washed with HEPES buffer (3x1 ml) before determining the absorbance of radium-223 on the column material using an HPGe detector (Ortec, Oak Ridge, TN).

The material removed 98.9% of radium-223 and daughter nuclides (Table 2).

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table 2

Average retention percentage of radium-223 for ceramic hydroxyapatite (n=3)

Samples Radium-223 Average Retention (%) Ceramic hydroxyapatite 98.9

Example 2. Purification of the target thorium conjugate in phosphate buffer on centrifuge columns with a cation exchange resin based on propylsulfonic acid and silica.

The trastuzumab-chelator conjugate, prepared as previously described (WO 2011/098611 A), was labeled with thorium-227 (forming the target thorium conjugate, TTC) using thorium-227, which was stored for 5 days in HCl after purification and therefore contained ingrown radium-223 and daughter decay products of radium-223. Each sample contained 0.21 mg TTS, 520 kBq thorium-227, and 160 kBq radium223 in 300 µl phosphate buffered saline, pH 7.4 (Biochrome PBS Dulbecco, Cat no L1825). The sample was added to a 15 mg propyl sulfonic acid silica cation exchange resin column. The columns were centrifuged (10,000 rcf, 1 min) and the eluate was collected. The distribution of thorium-227 (TTC) and radium-223 between the column and the eluate was determined using an HPGe detector (Ortec, Oak Ridge, TN).

The retention of TTS (represented by thorium-227) and radium-223 on the column was 5.5 and 99.1%, respectively (Table 3).

Table 3 Retention of the target conjugate of thorium (TTS) and radium-223 after purification on centrifuge columns with cation exchange resin

Amount of cation exchange resin (mg) TTS per column (%) radium-223 on column (%) 15 5.5 99.1

Example 3 Removal of radium-223 in citrate and phosphate buffer on centrifuge columns with cation exchange resin based on propylsulfonic acid and silica 160 kBq of radium-223 in 300 μl of 50 mM citrate buffer, pH 5.5, with 0.9% sodium chloride or phosphate buffer solution, pH 7.4 (Biochrome PBS Dulbecco, Cat no L1825) was added to a column of 60 mg propyl sulfonic acid silica cation exchange resin. The columns were then centrifuged (10,000 rcf, 1 min) and the eluate was collected. The distribution of radium-223 between the column and the eluate was determined using an HPGe detector (Ortec, Oak Ridge, TN).

The retention of radium-223 on the column was 96.5% for citrate buffer and 99.6% for phosphate buffer, respectively (Table 4).

Table 4

Retention of radium-223 after purification on centrifuge columns with cation exchange resin

Buffer type Average radium-223 per column (%) citrate 96.5 Phosphate 99.6

Example 4 Further Comparison of Selective Binder Materials.

Strontium calcium alginate gel beads, DSPG liposomes, ceramic hydroxyapatite, Zeolite UOP type 4A, and two cation exchange resins (AG50WX8 and SOURCE 30 S) were selected as materials for radium-223 uptake studies. Passive diffusive absorption of nuclides was tested on materials in the form of suspensions in the composition. Measurements were made with a germanium detector after 1 hour equilibration at 25° C. with shaking. The removal of free nuclides on gravity columns was also investigated.

Absorption of radium-223.

All materials removed radium-223 and progeny to some extent by passive diffusion absorption in the absorption range from 30.8±5.8 to 95.4±2.5% under selected experimental conditions. All materials tested were removed with radium-223 and progeny on a gravity column set to almost complete absorption. The results were significantly higher (~100%) and with minimal deviations (<1%) compared to the passive diffusive absorption of radium-223 for all materials tested except for the alginate gel beads (see Table 5).

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Table 5

Samples Average absorption of radium-223 by passive diffusion 1 (%) 1 Relative standard deviation of absorption of radium-223 by 1 passive 1 diffusion (%) Average absorption of radium-223 on the gravity column (%) 1 Relative standard deviation of radium-223 absorption at gravitational ι | column (%) | Liposomes . ⁹⁵ - ⁴ , 78.7 | 77.8 71.9 ^! 68.2 * 49.7 1 33.1 1 |.......................2,5....... ................................. -i i-i SOURCE 30S cation exchange resins 15.8 99.5 ο,ι i Ceramic hydroxyapatite 20.1 ......................98.9......... ............................... .................................0.7...... ................................................ Calcium alginate gel granules 9.7 8.2 20.7 Gel granules of atginate | strontium 16.7 - - 1 1 Zeolite UOP type |.........................................4A....... ................................... 7.4 - - I Gel granules atginata | calcium 1 1-7 - -i | AG50WX8 cation exchange | resin | 30.8 ^{5'8 _} 99.8 1__________________________________________________________________________________________________________________________________1 1 0.2 1 eleven

Various materials suitable for capturing the daughter isotopes of radium-223 have been identified. Strontium calcium alginate gel beads, DSPG liposome, ceramic hydroxyapatite, Zeolite UOP type 4A and two cation exchange resins (AG50WX8 and SOURCE 30 S) were tested and all materials were found to remove radium-223 and progeny.

DSPG liposomes showed excellent results in the passive diffusion uptake test, while other materials were suboptimal when used in the form of suspensions and for passive diffusion uptake. However, cation exchange resins and ceramic hydroxyapatite have proven to be excellent when used on gravity columns.

Example 5 Reduction of radiolysis.

The formation of hydrogen peroxide (H ₂ O ₂ ) in the aqueous phase of the composition was investigated as a measure of radiolysis in the presence and absence of ceramic hydroxyapatite, which was one of the materials shown to be effective in binding to radionuclides from solution. Radiolysis and the formation of free radicals in the aqueous phase can destroy the radionuclide complex and thus it is desirable to minimize the formation and amount of H ₂ O ₂ present. After 3 days, the concentration of H ₂ O ₂ in samples with ceramic hydroxyapatite was significantly lower than in control samples, and the absorption of ²²³ Ra and ²²⁷ Th from the solution was almost complete.

Way.

A UVmini-1240 single beam spectrophotometer (190-1100 nm) from Shimadzo (Kyoto, Japan) was used and the light transmission was recorded at 730 nm for H ₂ O ₂ concentration analyses. The photometric mode was used to measure the absorbance of the sample at a fixed wavelength (n=3). The cuvettes used were 1.5 ml (12.5 x 12.5 x 45 mm) Plastibrand disposable semi-micro cuvettes made of polystyrene.

0.5 mg/ml horseradish peroxidase solution and 2 mg/ml peroxidase substrate solution (diammonium salt of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) were prepared by dissolving in metal-free water. The enzyme peroxidase converts the peroxidase substrate from colorless to green with H ₂ O ₂ as the substrate. H ₂ O ₂ standards at 1.765, 0.882, 0.441, 0.221 and 0.110 mmol/l H ₂ O ₂ were prepared by diluting 30% (w/w) H ₂ O ₂ in metal-free water (n=3). The linearity of the standard curve was R ² =0.9995.

Samples consisted of 100 mg/ml ceramic hydroxyapatite in 250 µl 9 mg/ml sodium chloride, to which freshly prepared ²²⁷ Th solution was added to a concentration of 0.5 kBq/µl (n=3).

Analyzed two types of control samples; one negative control with ²²⁷ Th only and no binder and one positive control with binder but no radioactive source (n=3). The negative controls were analyzed to check the homogeneity of the radionuclides in the sodium chloride solution and the amount of H ₂ O ₂ formed in the absence of binder, and the positive controls were analyzed to check if a significant level of H 2 O 2 developed without the presence of radioactivity.

To calculate the percentage uptake of radionuclides in ceramic hydroxyapatite samples and the homogeneity of radionuclides in negative controls, each sample or control is measured

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Claims (22)

were measured on an HPGe detector before removing 60 µl of the supernatant. Samples, controls and standards were further prepared for H2O2 analysis by mixing 900 µl of 9 mg/ml sodium chloride with 50 µl of peroxidase substrate solution, 25 µl of horseradish peroxidase solution and 25 µl of the respective supernatant from sample, control and standard. Samples, control or standard were thoroughly mixed and immediately thereafter measured by spectrophotometry in the ultraviolet and visible region of the spectrum. For radioactive samples and control samples, the remaining volume of the sample was finally measured on the HPGe detector. The absorption of radionuclides in ceramic hydroxyapatite or the homogeneity of radioactivity in sodium chloride solution was calculated using HPGe spectra. The concentration of H ₂ O ₂ in the samples, standard and control samples were analyzed by spectrophotometry in the ultraviolet and visible spectral region at 730 nm at the time of the start of the countdown, after 3, 7, 10 and 14 days. Results. The measured level of H ₂ O ₂ formed during 14 days of storage in samples of suspended ceramic hydroxyapatite and freshly prepared ^227Th was significantly lower compared to negative control samples without ceramic hydroxyapatite (see drawing). Positive controls containing ceramic hydroxyapatite without radioactivity did not show H ₂ O ₂ formation beyond the statistical error of the method (see drawing). Passive diffusion absorption of freshly prepared ²²⁷ Th in ceramic hydroxyapatite suspension was 81±3% in 90 min of reaction. The subsequent uptake of ²²⁷ Th and ²²³ Ra generated by the ceramic hydroxyapatite was 99±5% and 102±12%, respectively, as measured after 14 days of incubation. The measured decrease in H ₂ O ₂ demonstrates reduced formation of radicals and oxidizing agents due to radiolysis of the containing solution. CLAIM 1. A method of forming a purified solution of at least one α-particle emitting thorium isotope intended for use in endoradionuclide therapy, including contacting a solution comprising at least one α-particle emitting thorium isotope and at least one radium isotope with at least one selective binder substance for the radium isotope and subsequent filtration of the solution of at least one emitting α-particles of the thorium isotope from at least one selective binder to remove at least one radium isotope, and the selective binder is selected from the group consisting of cation exchange resins and ceramic hydroxyapatite. 2. The method according to claim 1, characterized in that the α-emitting thorium isotope is provided in the form of a complex with a chelator, the chelator being conjugated to a specific antibody binder. 3. The method according to claim 1, characterized in that the selective binder is provided in the form of a solid or gel, or is attached to a solid or gel base. 4. The method according to claim 3, characterized in that the solid or gel base is provided in the form of at least one material selected from the group consisting of membranes, resin beads, gel beads, self-assembled lipid structures such as liposomes, microparticles, nanoparticles, powders, crystals, ceramics and polymeric structures or is attached to them. 5. The method according to claim 1, characterized in that the solution is brought into contact with the selective binder by means of a stream of solution passed through or through the selective binder or through or through the base on which the selective binder is immobilized. 6. The method according to claim 5, characterized in that the contact is provided by filtration, and the solution is passed through or through a selective binder or through or through a support on which the selective binder is immobilized. 7. The method according to claim 6, further comprising passing the stream of the above solution through a sterile filter membrane after filtration. 8. The method according to any one of claims 1 to 7, characterized in that the contact occurs within a period of less than 30 minutes, less than 10 minutes, less than 5 minutes, less than 1 minute, or no more than 30 seconds. 9. The method according to any one of claims 1 to 4, characterized in that the solution is brought into contact with the selective binder by adding the selective binder and the solution to a vessel, such as a sealed or partially sealed vessel. 10. The method according to claim 9, characterized in that the contact occurs within 30 minutes, more than 1 hour, more than 1 day or more. 11. A kit for creating a pharmaceutical preparation of at least one thorium isotope complex emitting α-particles intended for use in endoradionuclide therapy, the above-mentioned kit including: i) a solution of at least one α-emitting isotope of thorium and at least one isotope of radium; ii) at least one chelator; ii) a specific binding component, which is an antibody; iii) at least one selective binder for at least one radium isotope; wherein the α-emitting thorium isotope is or may be a coupled chelator that is or may be conjugated to a specific binder, the selective binder being selected from the group consisting of cation exchange resins and ceramic hydroxyapatite. 12. The kit according to claim 11, characterized in that the solution of at least one α-emitting thorium isotope and at least one radium isotope is in the first vessel, such as a vial, syringe, etc., and a chelator conjugated with a specific binding component , is in the second vessel. 13. A kit according to claim 11 or 12, characterized in that the selective binder is provided in the form of at least one filter, such as a syringe filter, through which a solution of the α-emitting thorium isotope can be passed after complexation by the chelator and optionally after conjugation with a specific binding component. 14. The kit according to claim 11 or 12, characterized in that the selective binder is provided in the form of or attached to at least one solid or gel base. 15. The kit according to claim 14, characterized in that the selective binder is in the first vessel. 16. The kit according to any one of claims 11 to 15, characterized in that the selective binder is adapted to be separated from the solution during the introduction of said solution. 17. A kit according to any one of claims 11 to 16, characterized in that it additionally includes a filter and/or a device for introducing the solution. 18. Kit according to any one of claims 11-17, characterized in that it includes a filter with a pore size of not more than 0.22 microns. 19. A kit according to any one of claims 11-18, characterized in that it includes an administration device comprising a solution of at least one bound α-particle emitting isotope of thorium and at least one isotope of radium, and the kit also includes a selective binder for the radium isotope in the form of a filter. 20. A device in the form of a disposable syringe and a syringe filter for introducing a solution of at least one α-particle emitting complex of a thorium isotope and at least one radium isotope, the device comprising a filter with at least one selective binder designed for the radium isotope and a selective binder the substance is selected from the group consisting of cation exchange resins and ceramic hydroxyapatite. 21. A method for the formation of an injection solution of a thorium isotope complex, including the steps: a) combining a first solution comprising a dissolved salt of an α-emitting thorium isotope and at least one radium isotope with a second solution comprising at least one chelator conjugated to at least one antibody; b) incubating the combined solutions at a suitable temperature between 0 and 50° C. for a period allowing the formation of a complex between the chelator and the α particle emitting thorium isotope, thereby forming a solution of at least one bound α particle emitting thorium isotope; c) contacting a solution of at least one bound α-particle emitting thorium isotope with at least one selective binder for at least one of the radium isotopes, the selective binder being selected from the group consisting of cation exchange resins and ceramic hydroxyapatite; d) separating a solution of at least one α-particle emitting thorium isotope complex from at least one selective binder. 22. The method according to claim 21, characterized in that steps c) and d) are carried out according to the method for forming a purified solution according to any one of claims 1 to 10. -