EA045142B1 - METHOD FOR OBTAINING A SUSPENSION OF RADIOACTIVE YTTRIUM PHOSPHATE PARTICLES - Google Patents

Description

Field and State of the Art

A method for producing a suspension of radioactive yttrium phosphate particles for the treatment of tumors, including solid tumors.

Any patents and publications mentioned herein are incorporated herein by reference.

The essence of the invention

The claimed method relates to the production of radioactive yttrium phosphate particles having a preferred size for interstitial use in solid tumors.

A method for producing yttrium phosphate particles is proposed, including:

preparation of reagents, including:

weighing a non-radioactive ⁸⁹ Y yttrium salt selected from the group consisting of yttrium chloride, yttrium nitrate, yttrium sulfate and yttrium bromide, and quantitatively transferring into a volumetric flask; adding deionized water;

stir until completely mixed; and withdrawing the ⁸⁹ Y salt solution from the volumetric flask into a syringe, passing the solution through a filter and collecting the solution into a sterile container; and preparation and filtration of reagents: 0.15 M Na ₂ HPO ₄ and 0.05 M HCl; storing these reagents at room temperature; and preparing a radioactive ⁹⁰ YCl ₃ solution by adding to a source vial containing a solution of ⁸⁹ Y salt and a sufficient volume of 0.05 M HCl to achieve recovery of the desired amount of radioactive material from the source vial; and carrying out the procedure for the synthesis of radioactive ( ⁹⁰ Y+ ⁸⁹ Y)PO ₄ , including adding H2O to a test tube for a microwave reactor with a sterile magnetic stirrer; and placing the reaction vessel on the magnetic stirrer plate; and with continuous stirring and adding 0.15 M Na ₂ HPO ₄ and adding a solution of ⁹⁰ Y ³⁺ , adding ⁹⁰ Y in 0.05 M HCl from the source ampoule; and recording the final pH value and transferring said test tube into a microwave reactor; and setting the reaction temperature in the range from 110 to 160°C and the reaction time from 1 to 20 hours, and starting the reactor; and performing the final steps of placing the particle-containing microwave reactor tubes into a centrifuge to obtain a loaded centrifuge, starting the centrifuge; and replacing the supernatant with sterile phosphate-buffered saline and repeating the final steps two more times; and removing excess supernatant from said tube.

In one embodiment, the method includes weighing non-radioactive YC1 ₃ -6H ₂ O and quantitatively transferring it into a volumetric flask; adding deionized water to the volumetric flask; stirring the volumetric flask until completely mixed to obtain a 1.0 M solution ^{of 89} YCl ₃ ; and during the procedure for the synthesis of radioactive ( ⁹⁰ Y+ ⁸⁹ Y)PO4, adding 1.0 ml of H2O to a test tube for a microwave reactor with a sterile magnetic stirrer; and placing the reaction vessel on the magnetic stirrer plate; and with continuous stirring, carrying out the following stages:

adding 2.67 ml of 0.15 M Na ₂ HPO ₄ ; and adding 0.32 ml of ⁸⁹ YCl ₃ solution; and adding up to 0.05 ml ^{of 90} Y in 0.05 M HCl from the source ampoule; and transferring said tube into a microwave reactor;

setting the reaction temperature to 150°C and the reaction time to 1 hour, and starting the reactor; and at the final stages, adjusting the pH of the solution of yttrium phosphate particles using 1.0N. NaOH until the pH ranges from 1.5 to 8 and remove the supernatant so that 1.0 ml remains in the tube.

In one embodiment, the method includes producing particles in bulk by:

weighing 3.03±0.15 g of non-radioactive (YC1 ₃ -6H ₂ O and quantitatively transferring into a 10 ml volumetric flask; adding 10 ml of deionized water to the 10 ml mark; stirring until completely mixed; and taking 8-10 ml 1, 0 M ⁸⁹ YCl ₃ into a syringe, passing the solution through a filter and collecting the solution in a sterile container; and preparing and filtering the reagents: 0.15 M Na ₂ HPO ₄ and 0.05 M HCl; and in the final stages:

adjusting the pH of the solution of yttrium phosphate particles using 1.0N. NaOH to pH value from 7 to 8; and removing the supernatant so that 1.0 ml remains in the tube.

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In addition, an alternative method has been proposed for obtaining a suspension of radioactive particles of yttrium phosphate, including:

combining a solution of yttrium salts selected from the group consisting of yttrium chloride, yttrium nitrate, yttrium sulfate and yttrium bromide with a solution of sodium phosphate, wherein the phosphate is in stoichiometric excess and the pH when combined is in the range of 1.5 to 8;

combining the above solutions with continuous stirring and heating in a closed vessel to a temperature of 110-160°C for 1 to 20 hours, while the conversion of soluble yttrium into insoluble YPO ₄ is more than 99.99% and a particle size distribution is achieved, wherein the particles have a size equal to or less than 2 μm, and wherein the YPO ₄ particles are suspended in a buffered saline solution at neutral pH, wherein the initial concentration of soluble yttrium in the combined solution is in the range of 0.5 to 3.0 mol/L, and the stoichiometric excess of phosphate is from 10 to 100% or the initial concentration of soluble yttrium in the combined solution is 0.08 mol/L and the stoichiometric excess of phosphate is 25%.

In one embodiment of the above method, the resulting suspension of radioactive particles consists of at least 90% of the total particle volume of particles with a size in the range of 0.1 to 2 μm.

In one embodiment, a particle suspension is prepared by preparing a particle precursor solution, stirring and heating said particle precursor solution to form YPO ₄ particles by controlled precipitation, and then treating the particles to produce a suspension of YPO ₄ particles in phosphate buffered saline at neutral pH.

In one embodiment, post-processing of the particle suspension consists of washing the particles 3 times with sterile phosphate-buffered saline (PBS) and removing or adding PBS to achieve the final desired volume.

In one embodiment, the yttrium phosphate particles in the particle suspension are radioactive and the particles are rendered radioactive by adding a soluble radioactive isotope to the particle precursor solution and homogeneously incorporating the isotopes into a matrix of insoluble yttrium phosphate particles.

Brief description of drawings

The above and other features and advantages of the invention will become more apparent with reference to the following detailed description of a preferred embodiment of the invention and the accompanying drawings.

In fig. Figure 1 shows the particle sizes determined after implementing the claimed method at pH 7.35, with the median particle size being 0.2450 μm.

In fig. 2 shows particle sizes at pH 7.4, with a median particle size of 0.1844 μm, with the particles shown in each of FIG. 1 and 2 provide interstitial effectiveness when applied in the cellular space.

The above descriptions of specific embodiments of the invention have been presented for illustrative purposes. They are not intended to be exhaustive or to limit the invention by the precise forms disclosed, and it will be understood that many modifications and variations are possible in light of the foregoing description and the accompanying drawings. The illustrative embodiment has been selected and described to best explain the principles of the invention and its practical application, enabling others skilled in the art to make a product best in accordance with the invention and various embodiments with various modifications as are suitable for the particular intended application.

Detailed Description of the Invention

A method for producing a suspension of radioactive yttrium salt particles, comprising several stages, including the use of a hydrothermal process in which a solution of a soluble yttrium salt selected from the group consisting of yttrium chloride, yttrium nitrate, yttrium sulfate and yttrium bromide is combined with a solution of sodium phosphate, wherein the phosphate is in stoichiometric excess and the pH when combined is in the range of 1.5 to 8 and preferably the pH is in the range of 7 to 8.

The solutions are combined with continuous stirring and rapid heating in a closed vessel to 150°C and the resulting mixture is kept for 1-10 hours, while the conversion of soluble yttrium to insoluble YPO ₄ is more than 99.99%, and the desired distribution is also achieved particles by size.

Preparation of YPO4 particles with the desired particle size distribution, suspended in a buffered saline solution at neutral pH suitable for direct injection into human or animal tissue.

A suspension of radioactive particles in which the particle size is less than 2 microns.

The suspension of radioactive particles included at least 90% of the particles, consisting of particles with a size in the range from 0.1 to 2 microns, of the total volume of particles.

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Claims (9)

In addition, the initial concentration of soluble yttrium in the combined solution ranges from 0.5 to 3.0 mol/L, and the stoichiometric excess of phosphate ranges from 10 to 100%. In addition, the initial concentration of soluble yttrium in the combined solution is 0.08 mol/L and the stoichiometric excess of phosphate is 25%. The method further includes the step of obtaining a suspension of particles formed by preparing a solution of a particle precursor, wherein the solution is stirred and heated, and conducting controlled precipitation to form YPO ₄ particles, followed by treating the particles to obtain a suspension of YPO ₄ particles in phosphate buffered saline solution at a neutral pH value suitable for injection into human or animal tissue. The method further includes the step of subjecting the particle suspension to post-treatment by washing the particles 3 times with sterile phosphate-buffered saline (PBS) and removing or adding PBS to achieve the final desired volume. The method further includes the step of subjecting the particle suspension to a post-treatment of adjusting the pH of the final solution with sodium hydroxide followed by removing excess solution or adding sterile PBS to achieve the final desired volume. The method further includes: a particle suspension in which the yttrium phosphate particles are radioactive, thereby serving as dispersed sources of therapeutic radiation for the treatment of cancer tumors and other diseases; The particles are given radioactivity by adding to the particle precursor solution a small amount of a soluble radioactive isotope, which is homogeneously incorporated into a particle matrix of insoluble yttrium phosphate. The method further includes a suspension of yttrium phosphate particles, in which the particle concentration is in the range of 40 to 125 mg/ml, to facilitate visualization using X-ray computed tomography, after combining in a ratio of 1:4 by volume with a biocompatible hydrogel or other suitable liquid solution - carrier, for injection into human or animal tissue. CLAIM 1. A method for producing yttrium phosphate particles, including: preparation of reagents, including: weighing a non-radioactive ⁸⁹ Y yttrium salt selected from the group consisting of yttrium chloride, yttrium nitrate, yttrium sulfate and yttrium bromide, and quantitatively transferring into a volumetric flask; adding deionized water; stir until completely mixed; and withdrawing the ⁸⁹ Y salt solution from the volumetric flask into a syringe, passing the solution through a filter and collecting the solution into a sterile container; and preparation and filtration of reagents: 0.15 M Na ₂ HPO ₄ and 0.05 M HCl; storing these reagents at room temperature; and preparing a radioactive ⁹⁰ YCl ₃ solution by adding to a source vial containing a solution of ⁸⁹ Y salt and a sufficient volume of 0.05 M HCl to achieve recovery of the desired amount of radioactive material from the source vial; and carrying out the procedure for the synthesis of radioactive ( ⁹⁰ Y+ ⁸⁹ Y)PO ₄ , including: adding H2O to a microwave reactor tube with a sterile magnetic stirrer; and placing the reaction vessel on the magnetic stirrer plate; and with continuous stirring and adding 0.15 M Na ₂ HPO ₄ and adding a solution of ⁹⁰ Y ³⁺ , adding ⁹⁰ Y in 0.05 M HCl from the source ampoule; and recording the final pH value and transferring said test tube into a microwave reactor; and setting the reaction temperature in the range from 110 to 160°C and the reaction time from 1 to 20 hours and starting the reactor; and implementation of the final stages, including: placing a test tube containing particles for a microwave reactor into a centrifuge to obtain a loaded centrifuge, starting the centrifuge; and replacing the supernatant with sterile phosphate-buffered saline and repeating the final steps two more times; and removing excess supernatant from said tube. 2. A method for producing yttrium phosphate particles according to claim 1, characterized in that it includes: weighing non-radioactive YC1 ₃ -6H ₂ O and quantitative transfer into a volumetric flask; adding deionized water to the volumetric flask; stirring the volumetric flask until completely mixed to obtain a 1.0 M solution ^{of 89} YCl ₃ ; and during the procedure for the synthesis of radioactive ( ⁹⁰ Y+ ⁸⁹ Y)PO4; adding 1.0 ml of H2O to a microwave reactor tube with a sterile magnetic stirrer; and placing the reaction vessel on the magnetic stirrer plate; and with continuous stirring it will - 3 045142 occurrence of the following stages: adding 2.67 ml of 0.15 M Na ₂ HPO ₄ ; and adding 0.32 ml of ⁸⁹ YCl ₃ solution; and adding up to 0.05 ml ^{of 90} Y in 0.05 M HCl from the source ampoule; and transferring said tube into a microwave reactor; setting the reaction temperature to 150°C and the reaction time to 1 hour, and starting the reactor; and in the final stages: adjusting the pH of the solution of yttrium phosphate particles using 1.0N. NaOH to a pH value in the range from 1.5 to 8; and removing the supernatant so that 1.0 ml remains in the tube. 3. A method for producing a portion of yttrium phosphate particles according to claim 2, characterized in that it includes producing particles in volume by: weighing 3.03±0.15 g of non-radioactive YC1 ₃ -6H ₂ O and quantitatively transferring it into a 10 ml volumetric flask; adding 10 ml of deionized water to the 10 ml mark; stir until completely mixed; and taking 8-10 ml of 1.0 M ⁸⁹ YCl ₃ into a syringe, passing the solution through a filter and collecting the solution in a sterile container; and preparation and filtration of reagents: 0.15 M Na ₂ HPO ₄ and 0.05 M HCl; and in the final stages: adjusting the pH of the solution of yttrium phosphate particles using 1.0N. NaOH to pH value from 7 to 8; and removing the supernatant so that 1.0 ml remains in the tube. 4. A method for producing a suspension of radioactive particles of yttrium phosphate, including: combining a solution of yttrium salts selected from the group consisting of yttrium chloride, yttrium nitrate, yttrium sulfate and yttrium bromide with a solution of sodium phosphate, wherein the phosphate is in stoichiometric excess and the pH when combined is in the range of 1.5 to 8; combining the above solutions with continuous stirring and heating in a closed vessel to a temperature of 110-160°C for 1 to 20 hours, while the conversion of soluble yttrium into insoluble YPO ₄ is more than 99.99% and a particle size distribution is achieved, wherein the particles have a size equal to or less than 2 μm, and where the YPO4 particles are suspended in a buffered saline solution at neutral pH, wherein the initial concentration of soluble yttrium in the combined solution is in the range of 0.5 to 3.0 mol/L, and the stoichiometric the excess of phosphate is from 10 to 100% or the initial concentration of soluble yttrium in the combined solution is 0.08 mol/l, and the stoichiometric excess of phosphate is 25%. 5. The method according to claim 4, in which the resulting suspension of radioactive particles consists of at least 90% of the total volume of particles from particles with a size in the range from 0.1 to 2 microns. 6. The method of claim 4, wherein the particle suspension is prepared by preparing a particle precursor solution, stirring and heating said particle precursor solution to form YPO4 particles by controlled precipitation, and then treating the particles to produce a suspension of YPO4 particles in phosphate buffered saline at neutral pH value. 7. The method of claim 6, wherein post-treatment of the particle suspension consists of washing the particles 3 times with sterile phosphate-buffered saline (PBS) and removing or adding PBS to achieve the final desired volume. 8. The method of claim 6, wherein post-treatment of the particle suspension consists of adjusting the pH of the final solution with sodium hydroxide, followed by either removing excess solution or adding sterile PBS to achieve the final desired volume. 9. The method of claim 4, wherein the yttrium phosphate particles in the particle suspension are radioactive and wherein the particles are rendered radioactive by adding a soluble radioactive isotope to the particle precursor solution and homogeneously incorporating the isotopes into a matrix of insoluble yttrium phosphate particles. -