RU2792618C1 - Method for producing a radiopharmaceutical preparation for the diagnosis and treatment of bone lesions of the skeleton in oncological diseases based on the complex of zoledronic acid with the isotope of rhenium-188 - Google Patents

Abstract

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to radiopharmaceuticals based on bisphosphonates, a method for their preparation, and can be used for diagnosis and treatment in oncology. The invention relates to the field of chemistry and medicine, in particular to a method for producing a radiopharmaceutical preparation for the diagnosis and treatment of bone lesions of the skeleton in oncological diseases based on a complex of zoledronic acid with a rhenium-188 radionuclide. First, a lyophilized reagent is obtained in the form of a lyophilizate by mixing an aqueous solution of zoledronic acid, a solution of tin halide and gentisic acid, non-radioactive sodium perrhenate in hydrochloric acid. Next, 1.8–2.2 ml of eluate sodium perrhenate (¹⁸⁸Re) in 0.9% sodium chloride solution is injected into the vial with lyophilisate, heated for 45–60 minutes at a temperature of 98°C, mixed and a concentrate is obtained which is cooled for at least 15 minutes. Within 90 minutes, the resulting concentrate is injected into an infusion system containing not more than 15 ml of a 0.9% sodium chloride solution to obtain an infusion form of the medicinal product.

EFFECT: production of a radiopharmaceutical based on a complex of zoledronic acid with a ¹⁸⁸Re radionuclide with increased storage stability for 120 minutes without loss of radiotherapeutic activity and preservation of RCP of at least 90% and, as a result, simplification and cheapening of preparation in the clinic and expansion of the possibility application in medical practice of radiopharmaceuticals based on the complex of zoledronic acid with ¹⁸⁸Re isotopes.

1 cl, 10 tbl, 10 ex

Description

The invention relates to the field of chemistry and medicine, in particular to radiopharmaceuticals based on bisphosphonates and a method for their preparation, and can be used for diagnosis and treatment in oncology, namely, in the treatment of bone metastases from tumors prone to metastasizing to the bones, multiple myeloma , as a means of eliminating hypercalcemia, as well as in the treatment of rheumatoid arthritis.

Radionuclide therapy (RNT) is a method of radiation therapy using open sources of ionizing radiation injected directly into the patient's body. Radioactive sources are introduced into the body in the form of radiopharmaceuticals (RPs). Osteotropic radiopharmaceuticals have the ability to bind to the bone matrix, concentrating mainly in foci with pathologically increased mineral metabolism (metastases, fracture zones, destruction sites). The therapeutic effect occurs due to the irradiation of β or α particles of tumor cells located in such foci and cells involved in the vicious circle of pathological bone damage. In cases where γ radiation is present in the radiation spectrum of a radionuclide, it is possible to visualize the foci of accumulation of therapeutic radiopharmaceuticals using a gamma camera using the SPECT/CT method.

Complexes of radionuclides with di- and polyphosphonates have an important property of selective accumulation in the skeleton, especially in areas of pathological bone formation. The advantage of using skeletal scintigraphy using the SPECT/CT method compared to radiographic diagnostics is the early detection of single and multiple foci of increased accumulation of a radioactive isotope in malignant neoplasms in the skeleton and bone metastases.

Phosphate complexes ^{of 99m} Tc are known, in particular polyphosphate, triphosphate and pyrophosphate [G.Subramanian, JGAgfee // Radiology - 1971. - Vol.99, - p. 192], also diphosphonates ^99m Ts, which have similar known properties [Schmitt G.Kh., Holmes R.A., Isitman A.T. // Radiology - 1974. - T.112, - p.733].

Currently, 99mTs-methylene diphosphonate ( ^99m Ts-MDP) and ^99m Ts-hydroxyethylidene diphosphonate ( ^99m Ts-HEDP, in the Russian literature - HEDP) are widely used in the world radiological practice for the diagnosis of bone metastases [WCEckelman, WAVolkert. // Int.J.Appl.Radiat.lsotopes-1982. - T.33, - p. 945].

Sodium pertechnetate, ^99mTc is obtained from a ^99Mo / ^99mTc generator. Tc(VII) is the most stable chemical state, but pertechnenate ions do not bind to chelating agents. To obtain stable compounds of reduced technetium, the use of various reducing agents is required, such as tin (II) ions, sodium borohydride, concentrated hydrochloric acid, sodium dithionite, hydrazine [Nuclear Medicine. Diagnosis and therapy // JC Harbert, WCEckelman, RDNeumann Eds. - Thieme Medical Publishers, Inc., New York, 1990, p. 218]. Most often, tin dichloride is used as a reducing agent, which is part of almost all preparations of ^99m Ts. Stannous chloride as a reducing agent is found in most radiopharmaceuticals used for diagnostics with ^99m Ts; it stabilizes the complex of reduced technetium with ligands.

All complexes of technetium with diphosphonates are osteotropic, and therefore the wording " ^99m Tc-phosphate complex" is generally accepted. For RNT, instead of ^99m Tc in the composition of phosphate complexes, rhenium-186 was used [SH Han, JM De Klerk, BA Zonnenberg. J Nucl Med. 2001 Mar;45(1):84-90], and in recent years the rhenium-188 isotope: rhenium-188-hydroxyethylidene diphosphonate ( ¹⁸⁸ Re-HEDP) [Knut Liepe, Joerg Kotzerke // Nucl Med Commun. 2007 Aug; 28(8): 623-30]; ¹⁸⁸ Re-methylenediphosphonate ( ¹⁸⁸ Re-MDP) [Angélica Barbezan, João A Osso Jr // 2011 International Nuclear Atlantic Conference - INAC 2011, Belo Horizonte, MG, Brazil, October 24-28, 2011].

Rhenium-188 is considered one of the most promising isotopes for radionuclide therapy. The half-life of rhenium-188 is 16.9 hours, while the energy of β-radiation, equal to 2.12 MeV, is sufficient to penetrate into the zone of the bone tumor focus to a depth of 5-10 mm. This makes it possible to achieve the expected therapeutic effect from the action of radiopharmaceuticals with a minimum of radiation damage to healthy tissue. Gamma radiation of rhenium-188 (Eγ=155 keV) enables scintigraphic observation of the distribution of the active isotope in tumor formations and in the body. In addition, being an element of Group VII of the Periodic Table, rhenium is capable of forming a number of complexes in various oxidation states. Obtaining the rhenium-188 isotope from the generator directly in the clinic reduces the problems with the logistics of high-activity radioactive radiopharmaceuticals and prepare radiopharmaceuticals directly in the clinical setting for each patient with individual characteristics.

Therefore, the choice of the radionuclide rhenium-188 as the basis of a radiopharmaceutical for the treatment of bone lesions of the skeleton in oncological diseases is extremely expedient.

Rhenium-188 is produced using a <188>W/<188>Re generator system. Rhenium-188 is formed by the decay of the parent radionuclide tungsten-188 and it is eluted with a 0.9% solution of sodium chloride, while rhenium-188 goes into solution in the form of sodium perrhenate (NaReO ₄ ). Rhenium-188 is also obtained using an extraction generator by extracting rhenium-188, which is formed as a result of the decomposition of tungsten-188, followed by evaporation of the solution and dissolution of the precipitate in a 0.9% sodium chloride solution.

Known colloid, <188>Re-Sn, and a method for its synthesis, proposed by researchers at Seoul University [JM Jeong et al. / Applied Radiation and Isotopes 52 (2000) 851-855]. To obtain <188>Re-Sn colloid, first, 0.5 ml of 0.1 M HCl containing 0.5-30 mg of SnCl ₂ ⋅2H ₂ O dissolved by nitrogen bubbling was placed in a vial under nitrogen atmosphere. When corking such a solution in a vial in a nitrogen atmosphere, its stability is maintained for 3 months. Then, 0.5 ml of <188>Re-perrhenate (approximately 30 MBq) was added to the vial as an eluate from the <188>W/<188>Re generator and kept at room temperature for 2 hours. The pH of the reaction mixture was then adjusted to neutral values using 0.2M phosphate buffer pH=8. Under these conditions, the labeling efficiency was over 95%. Significant advantages of this method compared to others are the production of a radiopharmaceutical composition at room temperature and a higher yield of labeled colloid. However, obtained by this technology is indicated only for RHT of synovitis and is not intended for RHT of bone lesions in cancer patients.

Rhenium, like technetium, forms complexes with common ligands. Studies have been conducted with the participation of methylenephosphonic acids, namely ethylenediamine-N,N,N',N'-tetrakis (methylenephosphoric acid, EDTMP; (ethylenediamine-N,N'-bis-(methylenephosphoric acid, EDBMP); (nitrilotris-( methylenephosphoric acid, NTMP) It was found that in the presence of stannous chloride, all ligands form protein complexes at pH <3 [Hashimoto K. Second Japanese-Russian seminar on technetium. Shizuoka, Japan, 1999, Abstracts, - p. 40].

In addition to diphosphonates, in recent years, bisphosphonates (BP) have been used in medical practice [Bonevolenskaya L.I. Bisphosphonates and osteoporosis. // Guide to osteoporosis / ed. L.I. Benevolenskaya - M., Binoche, Laboratory of Knowledge. - 2003, - ch.9, - p. 196-216.]. Studies of acute, subacute and chronic toxicity of BP have shown that they generally belong to the group of low-toxic compounds with relatively low levels of acute and chronic toxicity. No teratogenic, mutagenic, or carcinogenic properties were found in BF.

Zoledronic acid (ZA) is the latest generation bisphosphonate - the only bisphosphonate containing 2 nitrogen atoms and characterized by the highest affinity for bone lesions, including metastatic nature, and has the ability to inhibit bone resorption. It has been shown that ZK inhibits the activity and induces apoptosis of osteoclasts. ZK blocks osteoclastic resorption of mineralized bone and cartilage tissue, activated by bone tumors and metastases. In connection with these properties, ZK, unlike diphosphonates, is osteotropic to sites with both osteoclastic and osteoblastic metastases [Snegovoy A.V., Kononenko I.B. "Modern possibilities of osteomodifying therapy for bone metastases". breast cancer. No. 6 dated November 27, 2019, pp. 16-22].

Currently, for RNT with rhenium-188, diphosphonates are used, such as methylene diphosphonate (MDP), hydroxyethylidene diphosphonate (HEDP), in domestic practice - HEDP [Jak M.S.P., Han S.H. Zonnenberg B.A, et al. // J. Nucl. Med. - 1996. - Vol.37 - p.1511], 188Re-HEDP [Faintuch B.L., Faintuch S., Muramoto E. // Radiochim. Asta - 2003. - Vol.91, - p.607]. In particular, patent RU2567728C1 is known [Radiopharmaceutical drug with rhenium-188 for the treatment of bone lesions of the skeleton and a method for its production. 2006], including a method for obtaining a lyophilized reagent containing a 1st generation diphosphonate (HEDP), a reducing agent, an antioxidant, and an inactive rhenium salt, followed by the production of radiopharmaceuticals in clinical conditions by obtaining a complex with a salt of radioactive rhenium-188.

However, these complexes of diphosphonates with rhenium-188 have insufficiently high specificity and sensitivity in the diagnosis and effectiveness in the treatment of bone lesions. In addition, their use is limited to the predominant use in osteoblastic metastases.

Known drug Zoleren, ¹⁸⁸ Re in the form of a complex of HK with rhenium-188, obtained according to patent RU 2407746 C1 [Radiopharmaceutical agent for the diagnosis and treatment (therapy) of bone lesions of the skeleton and method for its production, 27.10.2010]. A feature of radionuclide therapy (RNT) of the obtained complex ZK- ¹⁸⁸ Re is a high level of its accumulation in bone metastases of various nature, which ensures the maximum intensity of local radiation exposure to ¹⁸⁸ Re beta radiation energy and, as a result, high efficiency of RNT of bone metastases ["Radionuclide therapy with drugs ¹⁸⁸ Re in oncology". K. Liepe, G. Limuris, V.V. Krylov, T.Yu. Kochetov. Oncology journal. 2018. Volume 1. No. 4. S. 34-42]. The presence of gamma radiation with an energy of 155 keV makes it possible to visualize the accumulation and distribution of radiopharmaceuticals using a gamma camera using the SPECT/CT method. The accumulation of radiopharmaceuticals in the body of a particular patient makes it possible to assess the feasibility of RNT by diagnosing using small doses of the ZK- ¹⁸⁸ Re complex before RNT, which allows you to personalize the approach to radiation therapy. The short half-life of rhenium-188 (16.9 hours) and the stability of the ZK- ¹⁸⁸ Re complex determine the safety of its use, ensure a rapid decrease in radioactivity in the patient's body, and minimize exposure to body tissues and surrounding persons. Zoledronic acid has a proven therapeutic effect and is the gold standard for the treatment of patients with multiple bone metastases.

Therefore, in the complex of ZK with rhenium-188, a double radiometabolic effect is achieved in RNT.

Methodology for the treatment procedure with Zoleren, ¹⁸⁸ Re: the calculation of the administered activity is carried out individually, the recommended dosage is 45 MBq/kg of the patient's body weight. The procedure is carried out in a specially equipped treatment room or in a ward using radiation-protective equipment. Zoleren, 188Re is administered through an intravenous catheter using an infusion pump over 15 minutes.

The indications of radiopharmaceuticals are: therapy of pain syndrome in patients with bone metastases of malignant tumors and rheumatoid arthritis. When planning RNT with Zoleren, ¹⁸⁸ Re, it must be taken into account that it contains a therapeutic dose of zoledronic acid (4 mg), therefore, the interval between the administration of “cold” zoledronic acid and Zoleren, ¹⁸⁸ Re should be at least 28 days. Continuation of therapy with radiopharmaceutical Zoleren, ¹⁸⁸ Re is indicated no earlier than 60 days after administration due to the need to restore blood parameters after radiation exposure.

The method for obtaining RFP Zoleren, ¹⁸⁸ Re is described in patent RU 2407746 C1, and is the closest to the proposed method according to the present invention, which consists in first lyophilizing the reagent obtained by mixing an aqueous solution of zoledronic acid and tin halide, possibly an antioxidant, a salt of the corresponding inactive isotope in hydrochloric acid, in a stream of inert gas, then a solution of sodium pertechnetate ( ^99m Tc) or a solution of sodium perrhenate ( ¹⁸⁸ Re) is added to the resulting lyophilisate to obtain a complex by mixing the obtained lyophilisate and solutions of radionuclides.

At the same time, the synthesis of radiopharmaceuticals with rhenium-188 consists in the fact that a vial with a lyophilizate containing zoledronic acid - 4.0 mg, tin dichloride - 1.5 mg, gentisic acid - 2.3 mg and sodium perrhenate - 0.045 mg is injected 1.5 ml of eluate of sodium perrhenate ( ¹⁸⁸ Re) in 0.9% sodium chloride solution, heated for 30 minutes, mixed, filtered at the outlet with a 0.22 μm filter and adjusted with a solution of 0.9% sodium chloride to a volume of 16.5 ml, get a solution of radiopharmaceuticals for intravenous administration, maintaining radiochemical purity - not less than 90% when stored for no more than 30 minutes.

The disadvantage of the obtained radiopharmaceutical of zoledronic acid with the isotope of rhenium-188 ( ¹⁸⁸ Re) according to the specified invention is low stability and therefore a short shelf life of 30 minutes, the presence of a precipitate that requires final filtration, leading to an uncontrolled loss of activity due to the part of the radiopharmaceutical remaining on the filter.

The technical objective of the claimed invention is the creation of new conditions for the preparation of radiopharmaceuticals based on zoledronic acid and radionuclide - ¹⁸⁸ Re, providing increased storage stability for a longer period, no sediment, elimination of final filtration and loss of activity.

The technical result of the claimed invention is the production of a radiopharmaceutical based on a complex of zoledronic acid with a ¹⁸⁸ Re radionuclide with increased storage stability for 120 minutes without loss of radiotherapeutic activity and preservation of RCP of at least 90% and, as a result, simplification and cheapening of preparation in the clinic and expansion of the possibility application in medical practice of radiopharmaceuticals based on the complex of zoledronic acid with ¹⁸⁸ Re isotopes.

The set technical task and the technical result obtained are achieved by the method claimed as an invention.

A method for producing a radiopharmaceutical for the diagnosis and treatment of bone lesions of the skeleton in oncological diseases, based on a complex of zoledronic acid with a rhenium-188 radionuclide, which consists in the fact that the reagent is first obtained by mixing an aqueous solution of zoledronic acid and a solution of tin halide in a vial in an inert gas stream , gentisic acid, non-radioactive sodium perrhenate in hydrochloric acid and then lyophilized; minutes at a temperature of 98 ° C, mix, obtain a concentrate, cool for at least 15 minutes, then after no more than 90 minutes or immediately injected into an infusion system containing no more than 15 ml of a 0.9% sodium chloride solution, the resulting solution is immediately injected intravenous drip to the patient.

Thus, the claimed method for obtaining a radiopharmaceutical preparation containing a radiotherapeutic complex of zoledronic acid and ¹⁸⁸ Re differs in that under aseptic conditions, 1.8 - 2.2 ml of the ¹⁸⁸ Re eluate (instead of 1 .5 ml in analogue), heated for 45 - 60 minutes (instead of 30 minutes), cooled for at least 15 minutes (instead of to room temperature), then the resulting concentrate is injected directly into the infusion system containing no more than 15 ml of a 0.9% solution sodium chloride (instead of - in an intermediate vial containing 16.5 ml of 0.9% sodium chloride solution, without final filtration (instead of filtering through a 0.22 micron filter).

Thus, according to the claimed invention, mainly 2.0 ml of sodium perrhenate eluate ( ¹⁸⁸ Re) in isotonic solution (0.9% sodium chloride solution) is introduced into the vial with lyophilisate (zoledronic acid and excipients), heated for 45-60 minutes, stirred , the output is 2 ml of concentrate with a shelf life of up to 120 minutes (preferably 90 minutes). Next, the concentrate from the vial is injected into an infusion system containing no more than 15 ml of a 0.9% sodium chloride solution and is administered to the patient slowly drip at a rate that provides an injection time of 15 minutes.

The following are specific examples of obtaining a radiopharmaceutical preparation, indicated in the text of the composition obtained on the basis of the claimed method, illustrating the invention, but not limiting it.

Received Generator "GREN-1".

The activity of the eluate according to the passport is 18.5 GBq.

Eluate activity as of the certification date: 30.8 GBq as of 01/24/2022

Generator elution 02/07/2022

Eluate activity 24.37 GBq/5 ml.

RHCh 99.9%

pH 5.15

[Example 1].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.04 GBq/ml

Preparation of the concentrate: 1.8 ml of the eluate from the generator with an activity of 2.04 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 45 minutes at a temperature of 98°C. Then 15 minutes of cooling and retention of the concentrate. Then samples were taken at the time of preparation (after cooling the vial for 15 min), after 60, 90 and 120 min.

Chromatographic systems: TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

Table 1 RHP Concentrate storage time At the time of preparation 60 min 90 min 120 min GWR, % 2.47 2.96 2.31 4.08 Perrhenate, % 2.0 2.04 2.10 2.15 RHP, % 4.47 5.0 4.41 6.23 pH 2.0

[Example 2].

Obtaining a concentrate in 2 vials with lyophilisate.

The activity of the eluate is 2.08 GBq/ml.

Preparation of the concentrate: 2.2 ml of the eluate from the generator with an activity of 2.08 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 60 minutes at a temperature of 98°C. Then the vial cooled down for 15 minutes. And then samples were taken at the time of preparation (after cooling the vial for 15 minutes), after 60, 90 and 120 minutes.

Chromatographic systems: TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

table 2 RHP Concentrate storage time At the time of preparation 60 min 90 min 120 min GWR, % 1.78 1.82 2.06 2.74 Perrhenate, % 3.26 2.73 3.62 4.59 RHP, % 5.04 4.55 5.68 7.33 pH 2.0

[Example 3].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.06 GBq/ml

Preparation of the concentrate: 2 ml of the eluate from the generator with an activity of 2.06 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 40 minutes at a temperature of 98°C. Then the vial cooled down for 15 minutes. And then samples were taken at the time of preparation (after cooling the vial for 15 minutes), after 60, 90 and 120 minutes.

Chromatographic systems: TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

Table 3 RHP Concentrate storage time At the time of preparation 60 min 90 min 120 min GWR, % 4.41 2.84 5.02 3.89 Perrhenate, % 2.03 1.85 1.85 3.33 RHP, % 6.44 4.69 6.87 7.22 pH 2.04

[Example 4].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.01 GBq/ml

Preparation of the concentrate: 2 ml of the eluate from the generator with an activity of 2.01 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 45 minutes at a temperature of 98°C. Then the vial cooled down for 20 minutes. And then samples were taken at the time of preparation (after cooling the vial for 15 minutes), after 60, 90 and 120 minutes.

Chromatographic systems: TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

Table 4 RHP Concentrate storage time At the time of preparation 60 min 90 min 120 min GWR, % 2.85 3.28 3.97 2.63 Perrhenate, % 2.25 1.95 2.0 3.45 RHP, % 4.10 5.23 5.97 6.08 pH Fl. 1 - 2.04; fl. 2 - 2.00

[Example 5].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.03 GBq/ml

Preparation of the concentrate: 2 ml of the eluate from the generator with an activity of 2.03 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 30 minutes at a temperature of 98°C. Then the vial was cooled down for 10 minutes. And then samples were taken at the time of preparation (after cooling the vial for 10 minutes). Then one vial was mixed with 15 ml of 0.9% NaCl 60 min after the preparation of the concentrate, and samples were taken 15 and 30 min after mixing. The second vial was mixed with 15 ml of 0.9% NaCl 120 min after the preparation of the concentrate, and samples were taken 15 and 30 min after mixing.

Chromatographic systems: TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

Table 5 RHP At the time of preparation Vial 1: preparation of the infusion form 60 minutes after preparation and 10 minutes of concentrate cooling Vial 2: preparation of the infusion form 120 minutes after the preparation of the concentrate Contact time with 15 ml 0.9% NaCl Contact time with 15 ml 0.9% NaCl 15 minutes 30 min 15 minutes 30 min GWR, % 3.22 2.77 4.51 3.75 4.14 Perrhenate, % 6.86 7.22 6.52 9.24 10.74 RHP, % 9.08 9.99 11.03 12.99 14.88 pH 2.06 2.72 2.72

[Example 6].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.01 GBq/ml

Preparation of the concentrate: 2 ml of the eluate from the generator with an activity of 2.01 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 60 minutes at a temperature of 98°C. Then the vial cooled down for 15 minutes. Then samples were taken at the time of preparation (after cooling the vial for 15 min), after 60, 90 and 120 min.

Chromatographic systems: TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

Table 6 RHP Concentrate storage time At the time of preparation 60 min 90 min 120 min GWR, % 2.57 4.06 2.64 2.58 Perrhenate, % 2.09 2.11 2.10 2.61 RHP, % 4.66 6.17 4.74 5.19 pH 2.00

[Example 7].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.09 GBq/ml

Preparation of the concentrate: 2 ml of the eluate from the generator with an activity of 2.09 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 40 minutes at a temperature of 98°C. Then 15 minutes of cooling and retention of the concentrate. Then samples were taken after 60, 90 and 120 min.

Chromatographic systems: for determination of radiopharmaceutical parameters - TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

Table 7 RHP Concentrate storage time Contact time with 15 ml 0.9% NaCl* At the time of preparation 60 min 90 min 120 min 15 minutes 30 min GWR, % 2.41 2.65 3.11 2.36 3.60 3.97 Perrhenate, % 1.95 2.59 1.95 2.19 7.93 8.66 RHP, % 4.36 5.24 5.06 4.55 11.53 12.63 pH 2.0 2.81

* The infusion solution was prepared 120 minutes after the preparation of the concentrate.

pH of concentrate 2.0; pH of the infusion solution 2.81.

[Example 8].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.02 GBq/ml

Preparation of the concentrate: 2 ml of the eluate from the generator with an activity of 2.02 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 45 minutes at a temperature of 98°C. Then the vial cooled down for 15 minutes. And then samples were taken at the time of preparation (after cooling the vial for 15 minutes). Then one vial was mixed with 15 ml of 5.0% dextrose (glucose) solution immediately after preparation of the concentrate, and samples were taken 15 and 30 minutes after mixing. The second vial was mixed with 15 ml of 5.0% dextrose (glucose) solution 60 minutes after the preparation of the concentrate, and samples were taken 15 and 30 minutes after mixing.

Chromatographic systems: TLC 5553 - acetone;

for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

Table 8 RHP At the time of preparation Vial 1: preparation of the infusion form immediately after preparation of the concentrate Vial 2: preparation of the infusion form 60 minutes after the preparation of the concentrate Contact time with 15 ml of 5.0% dextrose (glucose) solution Contact time with 15 ml of 5.0% dextrose (glucose) solution 15 minutes 30 min 15 minutes 30 min GWR, % 2.71 3.31 3.13 3.04 3.01 Perrhenate, % 2.37 14.83 15.54 18.51 23.04 RHP, % 5.08 18.14 18.67 21.55 25.05 pH - 2.77 2.77

[Example 9].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.05 GBq/ml

Preparation of the concentrate: 2 ml of the eluate from the generator with an activity of 2.05 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 60 minutes at a temperature of 98°C. Then the vial cooled down for 15 minutes. And then samples were taken at the time of preparation (after cooling the vial for 15 minutes). Then one vial was mixed with 15 ml of 10.0% mannitol solution immediately after preparation of the concentrate, and samples were taken 15 and 30 minutes after mixing. The second vial was mixed with 15 ml of 10.0% mannitol solution 60 minutes after the preparation of the concentrate, and samples were taken 15 and 30 minutes after mixing.

Chromatographic systems: TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values of 6 parallel.

Table 9 RHP At the time of preparation Vial 1: preparation of the infusion form immediately after preparation of the concentrate Vial 2: preparation of the infusion form 60 minutes after the preparation of the concentrate Contact time with 15 ml of 10.0% mannitol solution Contact time with 15 ml of 10.0% mannitol solution 15 minutes 30 min 15 minutes 30 min GWR, % 3.67 2.55 3.46 2.67 2.79 Perrhenate, % 2.08 7.30 7.52 13.37 15.39 RHP, % 5.75 10.85 10.98 16.04 18.18 pH - 2.64 2.67

[Example 10].

Obtaining a concentrate in 2 vials with lyophilisate.

Eluate activity - 2.05 GBq/ml

Preparation of the concentrate: 2 ml of the eluate from the generator with an activity of 2.05 GBq/ml was introduced into the vial with the lyophilisate. Heating in a bath for 45 minutes at a temperature of 98°C. Then the vial cooled down for 15 minutes. And then samples were taken at the time of preparation (after cooling the vial for 15 minutes). Then one vial was mixed with 15 ml of 0.9% NaCl immediately after preparation of the concentrate and samples were taken immediately and 15 minutes after mixing. The second vial was mixed with 30 ml of 0.9% NaCl immediately after preparation of the concentrate, and samples were taken immediately and 15 minutes after mixing.

Chromatographic systems: TLC 5553 - acetone; for the determination of HWR - Whatman 3MM - 0.9% NaCl.

Three samples were taken from each vial. The table shows the average values from 6 parallel

Table 10 RHP At the time of preparation Vial 1: preparation of the infusion form immediately after preparation of the concentrate Vial 2: preparation of the infusion form immediately after preparation of the concentrate Contact time with 15 ml
0.9% NaCl Contact time with 30 ml
0.9% NaCl Immediately after mixing 15 minutes after mixing Immediately after mixing 15 minutes after mixing GWR, % 2.33 2.84 2.83 3.33 3.41 Perrhenate, % 2.04 5.48 6.46 8.05 11.23 RHP, % 4.37 8.22 9.29 11.38 14.64 pH - 2.82 2.99

Conclusions:

The given information according to the experiments testify to the achievement of the specified technical result;

The necessary and sufficient time for the synthesis of the concentrate at a temperature of 45 - 60 minutes. In this case, the amount of impurities does not exceed 10% during 90-120 minutes of storage of the concentrate, that is, the stability of the concentrate and the radiopharmaceutical increases during longer storage.

The optimal conditions (from those tested) for the preparation of the infusion form: mixing with 15 ml of 0.9% NaCl, while the introduction of the infusion solution to the patient - immediately after its preparation and should not exceed 15 minutes. Under such conditions, the ROC value is no more than 9 - 10%.

Claims (1)

A method for producing a radiopharmaceutical preparation for the diagnosis and treatment of bone lesions of the skeleton in oncological diseases based on a complex of zoledronic acid with rhenium-188 radionuclide, which consists in the fact that the reagent is first obtained by mixing an aqueous solution of zoledronic acid and a solution of tin halide in a vial in an inert gas stream, gentisic acid, non-radioactive sodium perrhenate in hydrochloric acid and then lyophilized, then, under aseptic conditions, 1.8-2.2 ml of eluate sodium perrhenate [ ¹⁸⁸ Re] in 0.9% sodium chloride solution is injected into the vial with lyophilisate, heated 45-60 minutes at a temperature of 98 ° C, mix, obtain a concentrate, cool for at least 15 minutes, then after no more than 90 minutes or immediately injected into an infusion system containing no more than 15 ml of a 0.9% sodium chloride solution, the resulting solution is immediately administered intravenously drip to the patient.