Lyophilizate, pharmacuetical composition and method for preparing same

Abstract

The group of inventions relates to chemistry and the pharmaceutical industry, and more particularly to the field of radiopharmaceutical preparation. The group of inventions includes: a lyophilizate based on prostate-specific membrane antigen (PSMA) ligands for the preparation of a radiopharmaceutical composition, said lyophilizate containing PSMA I&T precursor, sodium acetate, gentisic acid and mannitol; a radiopharmaceutical composition in the form of an injectable solution for the treatment of prostate cancer, having a pH of 4.0-6.3 and containing the active substance 177Lu in the form of a 177Lu-PSMA I&T complex with a radioactivity concentration of 6000 MBq / ml, as well as sodium acetate, gentisic acid and mannitol; and a method for preparing said radiopharmaceutical composition from the proposed lyophilizate. The group of inventions expands the existing range of effective and safe radiopharmaceuticals for the targeted radionuclide therapy of castration-resistant prostate cancer.

Description

[0001] LYOPHILISATE, PHARMACEUTICAL COMPOSITION AND METHOD OF ITS PREPARATION

[0002] Description of the invention

[0003] Field of technology

[0004] The invention relates to the field of organic and medicinal chemistry, oncology, namely to the field of creating radiopharmaceuticals based on ligands to PSMA labeled with the radionuclide Lutetium-177 ( 177 Lu), for targeted radionuclide therapy (RNT) of castration-resistant prostate cancer (PCa).

[0005] Prostate cancer is the second most frequently diagnosed malignant neoplasm (13.5%) in men worldwide, with more than 1.2 million new patients diagnosed annually [1]. The number of patients with prostate cancer in the world who have been registered for 5 years has reached 3.7 million people (96.7 per 100 thousand population).

[0006] The success of treatment of any disease depends on the timeliness and completeness of its diagnosis. Prostate cancer is characterized by a number of biochemical and cellular markers that allow identifying and monitoring the degree of progression (or regression in case of successful therapy) of this disease. The presence of cellular markers also allows the use of receptor-specific therapy.

[0007] Prior art

[0008] In the treatment of oncological diseases, β-emitting radionuclides are widely used. One of the most promising β-emitters for cancer therapy is the radionuclide 177 LU, which has optimal nuclear physics characteristics for use in nuclear medicine. Since 177Lu emits both -particles and γ-quanta, it is ideal for both diagnostics and therapy of malignant neoplasms. The nuclear-physical and chemical properties of this radionuclide make it an ideal radioactive label for the needs of RNT. Its half-life of 6.71 days allows for the synthesis of labeled compounds and the transportation of radiopharmaceutical drugs (RPDs) to medical centers. 177 Lu also has an acceptable beta particle energy (E ма ks=0.497 MeV), soft accompanying gamma radiation (E т =113 keV (6.4%) and 208 keV (11%)). The decay product 177 Lu is a stable isotope 177 Hf. Relatively small mean free path of the P-particle 177LU In biological tissues (<2 mm) with localization of a significant number of radionuclide atoms in the immediate vicinity of the tumor cell, it ensures selective destruction of the tumor with minimal damage to surrounding tissues [2]. Nuclear medicine methods in the treatment of prostate cancer

[0009] Today, in accordance with the recommendations of the European Association of Urologists, the main methods of treatment for localized prostate cancer are: surgery (radical prostatectomy) and radiation therapy (external beam radiation therapy and brachytherapy). Brachytherapy (contact or interstitial radiation therapy) is a type of radiation therapy in which a radioactive radiation source is implanted and exerts an effect directly inside the affected organ. The main types of brachytherapy for prostate cancer are: low-power (low-dose, low-dose microsources containing isotopes 1-125, Pd-103, Cs-131 are implanted on a permanent basis) and high-power (high-dose, tumor irradiation occurs due to temporary contact with the prostate tissue of high-dose sources containing isotopes 1r-192, Co-60, Cs-137).The limited success of modern antitumor therapy in general, and prostate cancer therapy in particular, is explained [4] in part by the lack of specificity characteristic of many classes of cytotoxic agents and external beam radiation therapy. Molecularly targeted therapy, which has successfully entered the arsenal of modern antitumor therapy, has encountered the complex problem of acquired resistance, requiring an individual approach to select the optimal treatment tactics and improve patient survival.

[0010] In this regard, the strategy of targeted radionuclide therapy (TRNT), which is based on the selective delivery of radioactive isotopes to the tumor cell with minimal impact on surrounding healthy tissue, is becoming attractive throughout the world.

[0011] A real breakthrough was the development of targeted radionuclide therapy with radiopharmaceuticals based on PSMA ligands labeled with beta- or alpha-emitting radionuclides.

[0012] PSMA, or glutamate carboxypeptidase II, N-acetyl-a-linked acid dipeptidase I, or folate hydrolase, is a type II transmembrane glycoprotein belonging to the M28 peptidase family. This protein acts as a glutamate carboxypeptidase on a variety of substrates, including nutritional folate and the neuropeptide N-acetyl-L-aspartyl-L-glutamate [5].

[0013] PSMA is one of the most representative markers of prostate cancer, since this antigen is highly and very specifically expressed on the surface of tumor cells developing from the prostate gland (PG) at all stages of the disease [6]. It is located in the cytosol of prostate cells, and is associated with a membrane protein in the malignant process. The level of PSMA expression correlates with a decrease in the degree of tumor differentiation and is often elevated in metastatic and hormone-refractory tumors of the prostate gland. Unlike prostate-specific antigen (PSA), PSMA is not detected in the blood, which makes it an almost ideal marker of prostate cancer cells and an excellent target for radionuclide visualization and therapy [7]. PSMA is normally found in the secretory cells of the prostate epithelium, is extremely weakly expressed by cells of other organs (kidneys, salivary glands, small intestine) and is practically not found in benign neoplasms of the prostate gland.Despite its name, PSMA is not specific only to prostate tissue; this antigen is found in normal tissues of the salivary glands, duodenal mucosa, renal tubular cells, and a subpopulation of neuroendocrine cells in the crypts of the colon, as well as in tumor cells, such as some subtypes of transitional cell carcinoma, renal cell carcinoma, and colon cancer; however, PSMA expression in them is generally low.

[0014] Pharmaceutical compositions for the preparation of drugs for the treatment of prostate cancer based on ligands to PSMA, in particular, radiopharmaceuticals (RPs), are widely known.

[0015] The discovery of the effects of PSMA overexpression in malignant prostate tumors and its activation in metastatic and hormone-refractory carcinomas served as a trigger for the development of new radiopharmaceuticals for targeted RNT [6].

[0016] It is believed that 90 U,131 1 and 177 Lu are the most suitable candidates for inclusion in systemic radionuclide therapy. As 131 1, and 177 Lu, in addition to p-radiation, emit y-quanta during the decay process, whereas 90 U is a "pure" B-emitter.

[0017] Isotope 90 U is a B-emitter without γ-radiation emission, which results in low radiation exposure to both critical organs and the entire body. However, this feature also has its drawbacks - the absence of a γ-component does not allow tracking the distribution of this RFLP in the patient's body during and after a course of radionuclide therapy. In addition, this radionuclide is characterized by a relatively short half-life, an excessively high average energy of B-particle emission, as well as the complexity of technologies such as synthesis 90U-PSMA, as well as the production of radionuclides in the form of active pharmaceutical substances in a nuclear reactor or using a radionuclide generator 90 Sr / 90 Y, which is not mass-produced. Probably, these characteristics are the reason why radiopharmaceuticals are widely used in clinical practice 90 U-PSMA is not yet used. There is only one work in the open press in which the effectiveness of its use was assessed in 11 patients [8].

[0018] Currently, a clinical study of the radionuclide compound PSMA with a low molecular weight has been conducted - 131 1-M1P-1095. The disadvantage of this radiopharmaceutical for RNT was the need for a long hospital stay for the patient, as well as the phenomenon of hematological toxicity [9].

[0019] As already mentioned, the optimal radiation and physical characteristics for beta-emitting therapeutic radionuclides are possessed by 177Lu. Its y-radiation spectrum records the emission of gamma quanta with an optimal energy of 208 keV, which allows scintigraphic studies to be carried out after each therapeutic administration of the radiopharmaceutical to analyze its distribution, i.e., it makes it possible to predict the effectiveness of therapy. The radionuclide has a low average energy and a good radiation yield of p-particles, which ensures virtually local irradiation of metastases. As a result of systemic administration of the RFLP based on 177 Lu-PSMA critical organs (salivary glands and kidneys) receive the lowest radiation exposure compared to other radiopharmaceuticals

[0010] .

[0020] Radiopharmaceuticals based on α-methyl-2 ... 177 Lu, are labeled small molecule ligands of PSMA, which are called 177 Lu-PSMA-617 and 177Lu-PSMA I&T. In the molecule, PSMA-617, the use of the DOTA chelator allows the diagnostic isotope to be replaced 68 Ga for medical 177 Lu, however, the researchers noted lower accumulation of PSMA-617 compared to PSMA-11, in which 68 Ga is conjugated via the chelator HBED-CC (H,N'-bis(2-hydroxybenzyl)-ethylene diamine-L1,L2-diacetic acid). It should be noted that PSMA-11 cannot be labeled 177 Lu

[0011] . Another theranostic agent, PSMA I&T (Imaging & Therapy), chelated with DOTAGA (1,4,7,10-tetraazacyclododecane-1-(glutaric acid-4,7,10-triacetic acid), has comparable affinity for PSMA and highly efficient internalization to PSMA-11 and is suitable for widespread metastatic process as a theranostic agent

[0012] .

[0021] PSMA-617 and PSMA I&T labeled 177Lu have comparable biodistribution and resulting dosimetric characteristics. Therefore, both ligands can be used interchangeably. Currently, a large number of works on RNT with various PSMA-labeled ligands have been published. l77 Lu, in which the method received a positive assessment. At the same time, the volume of results obtained allowed the European Association of Nuclear Medicine (EANM) to publish unified guidelines for the implementation of radionuclide therapy with 177 Lu-PSMA

[0013] .

[0022] From RU 2730507 08 / 24 / 2020 a compound is known for obtaining a complex with a radionuclide label for diagnosing tumors expressing PSMA, of the general formula (I) as well as a complex for diagnosing tumors expressing PSMA, comprising a compound of formula (I) according to claim 1 with a radionuclide label, which is made up of triply charged metal cations selected from 1 1 'In, 67 Ga, 68 Ga,90 Y, 109 Pb, 203 Pb, ,05 Rh, l77 Lu, 213 Bi, 44 Sc, 47 Sc, 153 Sm, 16t Tb and 225 Ac and a pharmaceutical composition for diagnosing prostate tumors expressing PSMA, comprising a complex and a pharmaceutically acceptable carrier, filler or diluent for parenteral administration in a therapeutically effective amount. The therapeutically effective amount of the compound or composition according to the invention is selected in an amount sufficient to obtain the desired radiotherapeutic effect. When determining the dose for diagnostic imaging, it is necessary to take into account the specific activity of the radionuclide metal used.

[0023] In the article Oncological journal. 2020. Vol. 3. No. 1. P. 38-56 Nuclear medicine "Functional optimization of radionuclide pairs in prostate cancer theranostics" / / B. Ya. Narkevich, M. B. Dolgushin, V. V. Krylov, N. A. Meshcheryakova, D. I. Nevzorov, Federal State Budgetary Institution "N. N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, functional optimization of the composition of PSMA-based radiopharmaceutical pairs for radionuclide theranostics of castration-resistant prostate cancer was carried out. An analysis of the radiation-physical and dosimetric characteristics of 9 radionuclides for the diagnostic components of theranostic pairs and 6 radionuclides for the therapeutic components was carried out.

[0024] It has been shown that positron-emitting radionuclides should be considered optimal for diagnostics and monitoring of treatment effectiveness. 18 F and 68 Ga, and for radionuclide therapy - a beta-emitting radionuclide l77 Lu and alpha-beta emitting radionuclide225 Ace.

[0014]

[0025] EP3498308 of 19.06.2019 describes complexes comprising a PSMA targeting compound associated with a radionuclide such as, 177 Lu, 213 Bi, 225 Ace, 212 RЬ or 227Th, via a chelating moiety Z. The chelating group Z can be selected from the group consisting of acyclic chelators, cyclic chelators, cryptands, crown ethers, porphyrins or cyclic or non-cyclic polyphosphonates, DOTMP, EDTMP and bisphosphonate derivatives, DOTA, DOTA derivatives such as p-SCN-Bn-DOTA, pamidronate conjugated with DOTA, TCMC, a TCMC derivative such as p-SCN-Bz-TCMC, pamidronate conjugated with TCMC, antibody-DOTA conjugated, antibody-TCMC conjugated, HBED-CC, NOTA, NODAGA, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA and oxo-Do3A. These compounds and pharmaceutical compositions containing them can be used for medical purposes, for the treatment of prostate cancer, and the complexes provide dual targeting of cancer.

[0026] Several carrier molecules are available for targeting radioligand to PSMA.

[0027] 177 Lu in combination with PSMA-617 ( 177Lu-PSMA-617) is a compound in the most advanced stage of clinical development for use in radionuclide therapy.

[0028] This molecule works appropriately and provides appropriate tumor to normal tissue ratios for longer-lived (i.e. half-life of several days) radionuclides, including 177 Lu and 225 As, but at early time points (usually several hours after injection) shows high renal absorption.

[0029] This known technical solution also describes a solution containing a complex, where the solution can also be a pharmaceutical composition. Usually, an important element of a pharmaceutical composition is a buffer solution, which provides the necessary acidity of the preparation medium for the formation of a stable complex of the radionuclide with the carrier molecule, and is physiologically acceptable for infusion to patients.

[0030] In one embodiment, the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers and / or adjuvants. Acceptable pharmaceutical carriers include, but are not limited to, non-toxic buffers, fillers, isotonic solutions, etc. More specifically, the pharmaceutical carrier may be, but is not limited to, saline (0.9%), Ringer's lactate, 5% dextrose, 3.3% dextrose / 0.3% saline.

[0031] A physiologically acceptable carrier may contain an antiradiolytic stabilizer, such as ascorbic acid, which ensures the stability of the radiopharmaceutical during storage and transportation.

[0032] Disclosure of invention

[0033] The technical task of the claimed invention is to expand the arsenal of effective means, such as pharmaceutical compositions for the preparation of radiopharmaceuticals based on PSMA ligands labeled with a radionuclide. 177Lu for targeted radionuclide therapy of castration-resistant prostate cancer.

[0034] The technical result of the claimed invention in accordance with the set technical task is the expansion of the arsenal of effective and safe pharmaceutical compositions for the preparation of various pharmaceutical preparations, for example, radiopharmaceutical preparations based on PSMA ligands labeled with a radionuclide 177 Lu for targeted radionuclide therapy of castration-resistant cancer.

[0035] The stated technical task and technical result are achieved by the claimed group of inventions, including a lyophilisate based on PSMA ligands, including a PSMA I&T precursor and gentisic acid, for the preparation of a pharmaceutical composition, a radiopharmaceutical composition (radiopharmaceutical) for the treatment of oncological diseases, including an active substance 177LU In the form of a 177Lu-PSMA I&T complex and auxiliary substances, as well as a method for preparing a radiopharmaceutical composition in the form of an injection solution for the treatment of oncological diseases from a lyophilisate based on a solution of ligands to PSMA.

[0036] Thus, the technical task and the specified technical result are achieved by a composition in the form of a lyophilisate, which is the first invention of the claimed group, which is a composition in the form of a lyophilisate based on ligands to a prostate-specific membrane antigen (PSMA) for the preparation of a radiopharmaceutical composition in the form of an injection solution for the treatment of prostate cancer, characterized in that it includes a PSMA I&T precursor, sodium acetate, gentisic acid, mannitol in the following ratio of components: PSMA I&T 0.1 mg

[0037] Sodium acetate 20 mg

[0038] Gentisic acid 5 mg

[0039] Mannitol 1 mg

[0040] Another invention of the claimed group is a radiopharmaceutical composition in the form of an injection solution for the treatment of prostate cancer, characterized in that it has a pH of 4.0-6.3 and includes an active substance. 177 Lu as a complex 177 Lu-PSMA I&T with a volume activity of 250-6000 MBq / ml and excipients such as sodium acetate, gentisic acid and mannitol, in the following ratio of components per 1 ml:

[0041] 177 Lu as a complex 177 Lu-PSMA I&T 250 - 6000 MBq

[0042] Sodium acetate 10 mg

[0043] Gentisic acid 2.5 mg

[0044] Mannitol 0.5 mg

[0045] Another invention of the claimed group is a method for preparing a radiopharmaceutical composition in the form of an injection solution for the treatment of prostate cancer according to item 2 from a lyophilisate based on ligands to PSMA, characterized in that 2 ml of the solution are added to a closed glass vial with a volume of 5-15 ml with the lyophilisate [ 177 Lu]LuCh with a volume activity of 250-6000 MBq / ml, containing Lutetium-177 without a carrier, in a 0.04 M HCl solution, and mixed to form a reaction mixture, then the resulting reaction mixture in a tightly sealed vial is kept at a temperature of 70-95°C for 10-30 min, then the vial with the reaction mixture is cooled at room temperature for 10-30 min, after which 2 ml of the resulting solution is taken from the vial using a syringe, passed through a sterile membrane filter made of polyvinylidene fluoride (PVDF) with a pore diameter of 0.22 μm into a pre-sterilized hermetically sealed vial for the finished product.

[0046] The best embodiment of the invention

[0047] The invention is illustrated by the following examples, which do not limit the scope of the claims.

[0048] Thus, below are given specific examples illustrating the claimed group of inventions, which includes a cold kit based on ligands to PSMA in the form of a lyophilisate, a radiopharmaceutical composition obtained from it based on ligands to PSMA in the form of an injection solution, as well as a method for preparing a radiopharmaceutical composition in the form of an injection solution.

[0049] Example 1. Preparation of a solution based on ligands to PSMA in the form of a lyophilisate

[0050] To prepare a lyophilisate batch of up to 100 vials, weigh out 3.32 g of sodium acetate trihydrate (equivalent to 2.00 g of sodium acetate anhydrous), 0.5 g of gentisic acid, 0.1 g of mannitol and 0.01 g of PSMA I&T on an analytical balance. Transfer the selected samples to a 100 ml measuring flask using a chemical funnel and dissolve in water for injection, bringing the volume of the solution to 100 ml with constant stirring. Then select approximately 1 ml to determine the pH of the solution. The pH of the solution should be from 5.3 to 6.3.

[0051] The volume of the glass bottle type I is 5 - 15 ml. It is preferable to use a bottle with a volume of 10 ml.

[0052] Example 1 shows the total amount of reagents needed to make 100 vials:

[0053] Table 1

[0054] The resulting solution is filtered through a membrane sterilizing filter with a pore size of 0.22 μm. The filtered solution is packaged using a dosing device in 1 ml portions into glass vials for medicines. The contents of the vials are lyophilized. The lyophilization time depends on the specific equipment. Upon completion of the lyophilization process, the working chamber of the lyophilization dryer is filled with dry air. Then the vials are sealed with rubber stoppers and rolled with aluminum caps.

[0055] The results of studies of the quality of the obtained lyophilisate of three pilot industrial series No. 011221, 020322, 030322 confirm its stability when stored at a temperature of 2-10 C for at least 12 months (Table 2, Table 3, Table 4).

[0056] Table 2 - Results of the stability study of lyophilisate batch 011212:

[0057] Table 3 - Results of the stability study of lyophilisate batch 020303: Table 4 - Results of the study on the stability of the lyophilisate of the OZOZOZ series:

[0058]

[0059] Example 2. Results of studies of the method for preparing a radiopharmaceutical composition in the form of an injection solution for the treatment of prostate cancer from a lyophilisate based on ligands to PSMA and the stability of the resulting radiopharmaceutical composition

[0060] According to the description in Example No. 1, 3 pilot-industrial series of lyophilisate No. 121221, 020322, 030322 were produced. The preparation of the radiopharmaceutical composition was carried out according to the preparation method claimed as the invention and described above on p. 9 of the description: 2 ml of the solution are added to a closed glass vial with a capacity of 5-15 ml, preferably 10 ml, with a lyophilisate including PSMA I&T and functional additives such as gentisic acid, sodium acetate and mannitol [ 177 Ьи]ЬиС1з, containing 177Lu without a carrier, with a volume activity of 250 - 6000 MBq, solvent - 0.04 M HCl, then the resulting reaction mixture in a tightly sealed vial is kept at a temperature of 70-95 °C for 10-30 minutes, then the vial with the reaction mixture is cooled at room temperature for 10-30 minutes, after which 2 ml of the resulting solution is taken from the vial using a syringe, then the selected volume of the solution is passed through a sterile membrane filter made of PVDF (polyvinylidene fluoride) material with a pore diameter of 0.22 μm into a pre-sterilized hermetically sealed vial for the finished product.

[0061] If additional purification from cation impurities is required 177 Lu, a cation exchange cartridge (for example, Waters Sep-Pak CM Light catalog number WAT023531, or similar) can be installed in front of the membrane filter.

[0062] During the stability studies, a series of tests were conducted on the radiopharmaceutical composition obtained from it, studying its stability in terms of Radiochemical Purity (Table 5, Table 6, Table 7).

[0063] Table 5 - Yield of the reaction of synthesis of the labeled compound from the lyophilisate of series 011212 and the results of studying its stability

[0064] Table 6 - Yield of the reaction of synthesis of the labeled compound from the lyophilisate of series 020322 and the results of the study of its stability Table 7 - Yield of the reaction of synthesis of the labeled compound from the lyophilisate of series 030322 and the results of the study of its stability

[0065] The preparation of the radiopharmaceutical composition in each of the described cases was carried out without its purification on a cation-exchange cartridge. Consequently, the results of the study of radiochemical purity by thin-layer chromatography (TLC) at the time of preparation correspond to the value of the yield of the reaction of formation of the complex 177 Lu-PSMA I&T: not less than 99%.

[0066] The results of the study of the radiochemical purity of the labeled compound by the TLC method for 6 hours after preparation correspond to the standard value of at least 98.0%.

[0067] Thus, the claimed radiopharmaceutical composition ensures stability for at least 4 hours from the moment of preparation (when stored at room temperature), which ensures the quality, efficiency and ease of use of the manufactured drug in a medical institution.

[0068] Example 3. Results of preclinical studies of a radiopharmaceutical composition in the form of an injection solution for the treatment of prostate cancer from a lyophilisate based on ligands to PSMA

[0069] According to the description, in Example No. 1, 3 pilot industrial series of lyophilisate No. 121221, 020322, 030322 were produced. The products of these series were used to conduct preclinical studies of the radiopharmaceutical. l77 Lu-PSMA I&T.

[0070] Preclinical studies were conducted on experimental groups of laboratory animals (mice, rats, rabbits, guinea pigs).

[0071] The study of acute toxicity of the non-radioactive form of the radiopharmaceutical (lyophilisate) did not reveal any differences between the control and experimental groups, the survival rate in all groups was 100%. The animals maintained a healthy reaction to external stimuli, normal appearance and appetite. The dynamics of body weight was positive, the condition and weight of internal organs were normal.

[0072] The results of the subchronic toxicity studies of the non-radioactive form of the radiopharmaceutical (lyophilisate) showed a complete absence of any manifestations of toxic effects during 30 days of observation after the administration of the non-radioactive form of the radiopharmaceutical. No deviations from the physiological norm were noted in the parameters characterizing the blood composition and the functional state of organs and systems.

[0073] Subchronic toxicity of the finished dosage form of RFLP 177 Lu-PSMA I&T was studied on laboratory animals of two species (rodents and non-rodents) - 40 male Wistar rats with an average body weight of 198.0±3.3 g and 24 male Chinchilla rabbits with an average body weight of 1972±35.6 g. Two dosages of the finished dosage form of RFLP were studied. 177 Lu-PSMA I&T - minimum (ED МИ n) and maximum (EDmax) therapeutic doses for humans, determined by the activity of the radionuclide 177Lu, with equivalent conversion to laboratory animals with intravenous administration. In the format of repeated administration, the dose equivalent to the average dose (EDavg), cumulatively formed with three-time administration over three days, was estimated.

[0074] The results of the studies showed a complete absence of any external manifestations of toxic effects during 30 days of observation after the administration of the finished dosage form of the radiopharmaceutical. No deviations from the physiological norm were noted in the parameters characterizing the composition of whole blood. Biochemical analyses of blood serum showed no impairment of the liver, kidneys, or other organ systems of animals. No negative effects on the functional state of the cardiovascular and respiratory systems of laboratory animals were registered. The effect of the finished dosage form of the RFLP on the central nervous system of animals was not assessed, since the drug practically does not penetrate the blood-brain barrier.

[0075] Study of the allergenic effect of a non-radioactive form of the complex 177 Lu-PSMA I&T was conducted on 30 male albino guinea pigs with an average body weight of 365.6±27.0 g. The effect of two doses was studied: equivalent to the average human dose (ED) and exceeding the ED ten times (EDx10), determined by the concentration of the PSMA I&T compound. Research method: two-stage assessment of anaphylactogenic activity.

[0076] The results obtained from the conducted studies of the allergenic effect of the non-radioactive form of the complex 177 Lu-PSMA I&T allow us to conclude that the drug under study is not capable of causing a state of increased sensitivity when it enters the body. The non-radioactive form of the complex 177 Lu-PSMA I&T should be considered safe for use from an allergenic point of view.

[0077] The same conclusion can be made regarding the finished dosage form of the RFLP, since the inclusion of the radionuclide in the PSMA I&T molecule 177 Lu does not change its biological properties.

[0078] Study of the immunotoxic effect of a non-radioactive form 177 Lu-PSMA I&T was conducted on 30 male mice of the C57B1 / 6 line with an average body weight of 20.5±1.5 g. Two dosages were studied: exceeding the equivalent average dose for humans (ED) by ten (EDx10) and by a hundred (EDx100), determined by the concentration of the PSMA I&T compound. Research method: delayed-type hypersensitivity reaction, allowing to evaluate cellular immunity, as well as the risk of changing the allergy status. The results of the conducted studies of the immunotoxic effect of the PSMA I&T compound allow us to conclude that the studied drug has no modifying effect on immunogenesis when entering the body.

[0079] Lyophilisates for the preparation of RFLP 177Lu-PSMA I&T should be considered safe for use in terms of immunotoxicity. The same conclusion can be made regarding the finished dosage form of the RFLP, since the inclusion of the radionuclide in the PSMA I&T molecule 177 Lu does not change its biological properties.

[0080] Assessment of radiation doses to tissues and the whole body following intravenous administration of the finished dosage form of the RFLP 177 LU-PSMA I&T was calculated by extrapolation of pharmacokinetic data, which predicts similar accumulation in the adult human body.

[0081] The results of the predictive calculation of absorbed doses are probabilistic, since they are extrapolated from the body of laboratory animals to humans, and can be used to assess the overall dosimetric picture.

[0082] The highest values ​​of resident time indicated a short half-life of the drug and high accumulation and were characteristic of the kidneys, bladder and intestines, which coincides with the pharmacokinetic behavior of the studied drug.

[0083] The highest absorbed doses were recorded in the urinary bladder and kidneys due to the excretion of the drug by the urinary organs, as well as in the prostate gland due to its small size and morphology.

[0084] The radiation loads generated in the human body calculated in this study are comparable with the absorbed doses presented in the literature.

[0085] To assess the long-term deterministic effects on the whole body, an effective dose was used, taking into account the criticality share of the total amount of incorporated radionuclide.

[0086] The calculated effective dose in this study is 0.176 mSv / MBq, which, when administered with 5 GBq of activity, will form a dose of 0.88 Sv. This is less than 1 Sv, meaning that the drug can be considered safe to use with a high degree of certainty from the point of view of radiation safety.

[0087] The functional suitability of the radiopharmaceutical was assessed based on the results of a study of its pharmacokinetics and therapeutic action.

[0088] Pharmacokinetic studies of RFLP 177 Lu-PSMA I&T in normal animals was performed on 25 male BALB / c mice and 25 male Wistar rats.

[0089] A study of the dynamics of distribution, accumulation and excretion in animals under normal conditions showed that in the absence of a pathological target focus in the body, the administered drug actively migrates from the blood into organs and tissues and accumulates in the kidneys, spleen and salivary glands.

[0090] The drug is excreted most intensively during the first three hours. 72 hours after administration, no more than 3-5% of the administered activity remains in the animal's body.

[0091] Pharmacokinetic studies of RFLP 177 Lu-PSMA I&T in animal models of pathology were performed on 25 male nu / nu mice with subcutaneous xenografts of human prostate cancer line 22RV 1.

[0092] A study of the dynamics of distribution, accumulation and elimination in animals with a pathology model showed a high engraftment rate of histologically confirmed subcutaneous 22RV1 xenografts, which began to be visualized and palpated on the 26th day after cell transplantation.

[0093] The results of the study are presented in Tables 8, 9.

[0094] Table 8 - Dynamics of distribution of RFLP 177 Lu-PSMA I&T in nu / nu mice with 22RV1 prostate cancer xenograft (% of injected activity per whole organ or tissue)

[0095] Table 9 - Dynamics of distribution of RFLP I77 Lu-PSMA I&T in nu / nu mice with 22RV1 prostate cancer xenograft (% of injected activity per 1 g of organ or tissue)

[0096] The administered drug actively migrates from the blood into organs and tissues and accumulates in the kidneys, spleen and salivary glands, as well as xenografts (reached a peak in the interval of 3-24 hours after administration, amounting to 5.22±0.36 and 4.93±0.93% of the administered activity / g, respectively). The intensity of excretion is slightly reduced, compared to normal mice, which is associated with the retention of the drug in the modeled pathological focus. Therefore, the specificity of the studied radiopharmaceutical to malignant neoplasms of the prostate gland, characterized by overexpression of receptors to PSMA, is demonstrated by very high accumulation and retention in tumor foci. Therapeutic action of RFLP ,77Lu-PSMA I&T in an animal model of pathology was assessed in 30 male nu / nu mice bearing subcutaneous xenografts of the 22RV1 human prostate cancer line.

[0097] The data on the research results are presented in Table 10:

[0098] Table 10 - Evaluation of the therapeutic effect of radiopharmaceuticals in mice with subcutaneous xenografts of human prostate cancer line 22RV1

[0099] Industrial applicability

[0100] The presented results of the studies demonstrated the dose dependence of the therapeutic effect of the radiopharmaceutical. Two dosages of the radiopharmaceutical (EDsht and EDt ah) were studied, which are equivalent to the administration to humans of the minimum (Dtsh) and maximum (Dmax) therapeutic doses (28.6 and 114.3 MBq / kg, respectively).

[0101] Statistically reliable confirmation of inhibition of tumor growth in animals of experimental groups was obtained.

[0102] Animals in the EDtakh group also showed positive values ​​for the tumor regression coefficient at all observation periods.

[0103] Thus, the RFLP ,77 Lu-PSMA I&T should be recognized as meeting the criterion of functional suitability in terms of achieving a therapeutic effect.

[0104] LIST OF REFERENCES

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Claims

CLAUSES OF THE INVENTION 1. A lyophilisate based on ligands to prostate-specific membrane antigen (PSMA) for the preparation of a radiopharmaceutical composition in the form of an injection solution for the treatment of prostate cancer, characterized in that it includes a PSMA I&T precursor, sodium acetate, gentisic acid, mannitol in the following ratio of components: PSMA I&T 0.1 mg Sodium acetate 20 mg Gentizoic acid 5 mg Mannitol 1 mg 2. A radiopharmaceutical composition in the form of an injection solution for the treatment of prostate cancer, characterized in that it has a pH of 4.0-6.3 and includes an active substance I77 Lu as a complex 177 Lu-PSMA I&T with a volume activity of 250-6000 MBq / ml and excipients such as sodium acetate, gentisic acid and mannitol, in the following ratio of components per 1 ml: 177 LU In the form of a complex 177Lu-PSMA I&T 250 - 6000 MBq Sodium acetate 10 mg Gentisic acid 2.5 mg Mannitol 0.5 mg 3. A method for preparing a radiopharmaceutical composition in the form of an injection solution for the treatment of prostate cancer according to paragraph 2 from a lyophilisate based on ligands to PSMA according to paragraph 1, characterized in that 2 ml of the solution are added to a closed glass vial with a volume of 5-15 ml with the lyophilisate according to paragraph 1 [ 177Lu]LuCl3 with a volume activity of 250-6000 MBq / ml, containing Lutetium-177 without a carrier, in a 0.04 M HCl solution, and mixed to form a reaction mixture, then the resulting reaction mixture in a tightly sealed vial is kept at a temperature of 70-95°C for 10-30 minutes, then the vial with the reaction mixture is cooled at room temperature for 10-30 minutes, after which 2 ml of the resulting solution are taken from the vial using a syringe, passed through a sterile membrane filter made of polyvinylidene fluoride (PVDF) material with a pore diameter of 0.22 μm into a pre-sterilized hermetically sealed vial for the finished product.

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