RU2432965C1 - Method of obtaining radiopharmaceutical for radionuclide therapy - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining preparations, labelled with rhenium-188 radionuclide, and can be used for obtaining radiopharmaceuticals, used in radionuclide therapy. Method lies in obtaining sterile solution, which consists of ligand, reducer and antioxidant, into which later non-radioactive rhenium in form of sodium perenate (NaReO₄) is introduced. Obtained solution is neutralized, filtered, frozen and liophilically dried with further introduction of radioactive rhenium-188 (Na¹⁸⁸ReO₄) with reaction of complex-formation of ¹⁸⁸Re with ligand.

EFFECT: invention makes it possible to obtain sterile radiopharmaceutical, time of preparation of which is reduced to 30-60 minutes due to simplification of technological cycle to one stage.

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Description

The invention relates to nuclear medicine, and in particular to methods for producing preparations labeled with a radionuclide, and can be used to obtain radiopharmaceuticals used in radionuclide therapy.

A known method of producing diphosphonate labeled ¹⁸⁸ Re [1]. A method of obtaining a labeled diphosphonate is as follows. 15 mg of 1-hydroxyethylidene diphosphonic acid sodium salt (Na ₂ HEDP), 4.5 mg of tin chloride (SnCl ₂ · 2H ₂ O) and 4.0 mg of gentisic acid are mixed in a vial. The resulting mixture was dissolved in an appropriate amount of distilled water, frozen and freeze-dried. To the dried mixture was added 1.0 ml of a solution containing 0.01-0.1 mg of inactive ammonium perrenate (NH ₄ ReO ₄ ) and 1.0 ml of radioactive sodium perrenate (Na ¹⁸⁸ ReO ₄ ). The mixture is then heated in a boiling water bath for 15 minutes. After that, the mixture is cooled to room temperature and the pH is adjusted to 5-6 by adding 1 ml of a 0.3 M sodium acetate solution.

The binding of ¹⁸⁸ Re to the ligand (Na ₂ HEDP) is 95.2-95.6%. The stability of the complex compound ¹⁸⁸ Re-Na ₂ HEDP is maintained for 2 hours. In the following terms, the complex is destroyed and the amount of ¹⁸⁸ Re bound to the ligand after 3 hours is about 94%, after 24 hours - about 93%.

The disadvantage of this method is the difficulty of obtaining the drug in a clinical setting and its relatively low stability.

A known method of producing diphosphonate labeled with ¹⁸⁸ Re [2], applicable in laboratory conditions. The essence of the method is that in a mixture of reagents consisting of 2-20 mg (0.01-0.15 M) of sodium salt of 1-hydroxyethylidene diphosphonic acid (Na ₂ HEDP), 2-5 mg (0.005-0.020 M) of chloride tin (SnCl ₂ · 2H ₂ O) and 0.5-5 mg (3 · 10 ^-3 · 3,5 · 10 · 2 ^-2 M) gentisic acid, add perrenate solution ( ¹⁸⁶ Re or ¹⁸⁸ Re) containing stable rhenium with concentration of 5 · 10 ^-6 -2 · 10 ^-3 M. The resulting mixture is heated and kept at 80-100 ° C for 10-30 minutes. Then it is cooled and the pH of the solution is adjusted to 5.0-6.0. The radiochemical impurities of perrenate and rhenium dioxide in the preparation did not exceed 1.5%.

The disadvantage of this method is the difficulty of obtaining the drug in a clinical setting.

The prototype of the proposed technical solution is the method [3], which consists in the fact that in the first stage a sterile solution is prepared containing a mixture of radioactive sodium perrenate (Na ¹⁸⁸ ReO ₄ ) with a volume activity of 148 to 2960 MBq / ml and non-radioactive sodium perrenate (NaReO ₄ ) with a concentration of 10 ^-4 -10 ^-3 mol / L. In the second stage, the prepared solution is added to a lyophilized reagent mixture, which includes a ligand (1-hydroxyethylidene diphosphonic acid), a reducing agent (SnCl ₂ · 2H ₂ O) and an antioxidant (ascorbic acid). Then the mixture is heated and maintained at 90-100 ° C for 15-30 minutes. In the third stage, the mixture is cooled and neutralized to a pH of not more than 7. As a result, a sterile injectable radiopharmaceutical is obtained.

The disadvantage of this method is the technological complexity, which leads to an increase in the duration of its preparation in a clinical setting. The complexity is due to the presence of three stages of obtaining a radiopharmaceutical. To obtain it in a clinic, you must have three bottles with sterile reagents: one bottle with a lyophilized mixture containing a ligand, a reducing agent and an antioxidant; another bottle with stable rhenium in the form of sodium perrenate and a third bottle with a solution to neutralize the radiopharmaceutical. The presence of three vials of reagents significantly increases the cost of the final product (radiopharmaceutical) and its preparation time, which leads to an undesirable increase in the exposure of clinical personnel.

The technical result of the present invention is to simplify the method of producing a radiopharmaceutical drug due to the effect obtained by combining non-radioactive (NaReO ₄ ) and radioactive (Na ¹⁸⁸ ReO ₄ ) rhenium with a lyophilisate under the conditions of one stage. At the same time, it seems possible to reduce the preparation time of a sterile radiopharmaceutical to 30-60 minutes by simplifying the process cycle to one stage.

The essence of the invention lies in the fact that in the method, including obtaining a sterile solution consisting of a ligand, a reducing agent and an antioxidant, non-radioactive rhenium is introduced in the form of sodium transfer (NaReO ₄ ). The resulting solution was neutralized, filtered, frozen and freeze-dried, followed by the introduction of a solution of radioactive rhenium-188 (Na ¹⁸⁸ ReO ₄ ). Then heated to the manifestation of the reaction of formation of the complex compound ¹⁸⁸ Re with the ligand. After cooling, the resulting radiopharmaceutical is suitable for use in a clinic.

Examples of the method.

Example 1

In a round-bottomed flask with two mouths with a capacity of 250 ml, equipped with a dropping funnel and a magnetic stirrer, 10 ml of a 20% solution of 1-hydroxyethylidene diphosphonic acid monopotassium salt (2 g, 8.16 · 10 ^-3 mol) are placed, 100 ml of water are added ( KOEDF - ligand), add 1.12 g (5.91 · 10 ^-3 mol) of tin dichloride (SnCl ₂ ) - (reducing agent) and mix until it is completely dissolved. To the resulting solution was added 0.7 g (3.97 · 10 ^-3 mol) of ascorbic acid (antioxidant) and stirred until complete dissolution. Then add 0.0365 g (1.355 · 1010 ^-4 mol) of sodium perrenate (NaReO ₄ ) and mix for 20 minutes. The resulting mixture was titrated with 0.1 M sodium hydroxide (NaOH) solution to a pH of 3.0. The solution was adjusted to a total volume of 150 ml, stirred for 10 minutes and filtered through a millipore filter with a pore size of 0.22 μm. The resulting solution is packaged in injection bottles with a capacity of 10 cm ³ in 1.5 ml. The contents of the vials are frozen at the temperature of liquid nitrogen and placed in a sublimator chamber cooled to -20 ° C. In the chamber create a pressure of 0.1-0.2 mm RT. column using a vacuum pump. Under these conditions, freeze drying is carried out for 23 hours, the chamber temperature is raised to + 20 ° C and drying is carried out for 1 hour. 5 ml of a solution of radioactive rhenium-188 (Na ¹⁸⁸ ReO ₄ ) is introduced into the contents of the vial, stirred until the contents of the vial are completely dissolved, heated in a boiling water bath to 95-100 ° C and incubated for 30 minutes to carry out the formation of complex compound ¹⁸⁸ Re with a ligand, cooled to room temperature. After cooling, the radiopharmaceutical solution is ready for injection.

Example 2

In a round-bottomed flask with two mouths with a capacity of 250 ml, equipped with a dropping funnel and a magnetic stirrer, 10 ml of a 20% solution of 1-hydroxyethylidene diphosphonic acid monopotassium salt (2 g, 8.16 · 10 ^-3 mol) are placed, 100 ml of water are added ( KOEDF - ligand), add 1.12 g (5.91 · 10 ^-3 mol) of tin dichloride (SnCl ₂ ) - (reducing agent) and mix until it is completely dissolved. To the resulting solution was added 0.7 g (3.97 · 10 ^-3 mol) of ascorbic acid (antioxidant) and stirred until complete dissolution. Then add 0.0365 g (1.355 · 10 ^-4 mol) of sodium perrenate (NaReO ₄ ) and mix for 20 minutes. The resulting mixture was titrated with 0.1 M sodium hydroxide (NaOH) solution to a pH of 3.0. The solution was adjusted to a total volume of 150 ml, stirred for 10 minutes and filtered through a millipore filter with a pore size of 0.22 μm. The resulting solution is packaged in injection bottles with a capacity of 10 cm ³ in 1.5 ml. The contents of the vials are frozen at the temperature of liquid nitrogen and placed in a sublimator chamber cooled to -20 ° C. In the chamber create a pressure of 0.1-0.2 mm RT. column using a vacuum pump. Under these conditions, freeze drying is carried out for 23 hours, the chamber temperature is raised to + 20 ° C and drying is carried out for 1 hour. 5 ml of a solution of radioactive rhenium-188 (Na ¹⁸⁸ ReO ₄ ) is introduced into the contents of the vial, stirred until the contents of the vial are completely dissolved, heated in a boiling water bath to 95-100 ° C and incubated for 60 minutes to carry out the reaction of complexation ¹⁸⁸ Re formation with a ligand, cooled to room temperature. After cooling, the radiopharmaceutical solution is ready for injection.

Confirmation of the technical result

As a result of combining non-radioactive and radioactive rhenium-188, a new technical result is obtained in the present invention. It consists in simplifying the method of obtaining a radiopharmaceutical, which consists in obtaining a radiopharmaceutical in one stage instead of three, as was done by the prototype. At the same time, the stage of neutralization of the finished radiopharmaceutical is excluded. The proposed solution allows to reduce the cost of the radiopharmaceutical, to reduce the time of its preparation, which can significantly reduce the dose to the medical staff while receiving the labeled drug.

1. Lin W.Y., Hsieh J.F., Lin C.P., Hsieh B.T., Ting G., Wang S.J. and Knapp F.F. Effect of Reaction Conditions on Preparations of Rhenium-188 Hydroxyethylidene Diphosphonate Complexes. Nucl. Med. Biol., 1999, V.26, P.455-459.

2. Pipes D.W. Preparation of rhenium phosphonate therapeutic agents for bone cancer without purification. U.S. Patent No. 5021235 (1991).

3. Basmanov VV, Kolesnik OV A method of obtaining a radiotherapeutic drug. Auth. Testimonial. No. 2164420 (2001).

Claims (1)

A method of obtaining a radiopharmaceutical for radionuclide therapy, comprising obtaining a sterile solution consisting of a ligand, a reducing agent and an antioxidant, characterized in that non-radioactive rhenium is introduced into the solution in the form of sodium transfer (NaReO ₄ ), the resulting solution is neutralized, filtered, frozen and freeze-dried, followed by the introduction of a solution of radioactive rhenium-188 (Na ¹⁸⁸ ReO ₄ ) and carry out the complexation reaction of ¹⁸⁸ Re with a ligand.