Way of reception of microspheres labeled with radionuclide

FIELD: medicine.

SUBSTANCE: invention concerns a way of reception of radioactive microspheres and can be used for reception of radiodrugs for radionuclide therapy of malignant neoplasms. The way of reception labelled a radionuclide of microspheres includes an emulsification of a solution of an albumin in vegetable oil, the further thermal processing of an emulsion and its filtration. Thus stable isotope Pd and a radionuclide 103Pd, in the form of a chloride palladium in 0.1 M a hydrochloric acid solution are admixed with albumin microspheres. The received admixture is processed with ultrasound before reception of homogeneous suspension then it is maintained at a room temperature within 18-24 hours. Microspheres are allocated from an admixture with a centrifugation with the subsequent restoration by Hydrosodium sulfitum. Fraction of microspheres with a diametre 20-40 micron is used.

EFFECT: reception of microspheres of an albumin with high specific activity.

2 ex, 1 tbl

 

The invention relates to medicine, namely to methods for producing labeled with radioactive isotopes, drugs, and can be used to produce radiopharmaceuticals used in radionuclide therapy.

A method of obtaining particles of hydroxyapatite (0.5-40 microns labeled with radionuclides186Re,153Sm156Sm [1]. This method is carried out in two variants with chelate ligands complexing agents, such as phosphonates, carboxylates or aminocarboxylate. In the first embodiment synthesize the compound of the ligand with the selected radionuclide, which is then attached to the microparticle-hydrophosphate through the atom of calcium. The second option synthesize compound ligand with hydrophosphination and then injected radioisotope with panelhanterare (for example, when the synthesis of compounds labeled samarium-153). Then, the obtained particles are washed by centrifugation or filtering.

The disadvantage of this method is the complexity of the synthesis of ORGANOMETALLIC compounds, especially for participating in the synthesis of radioactive substances with high activity.

A method of obtaining radioactive microspheres of glass the size of 3-30 microns, such as lithium silicate or potassium silicate, lithium or potassium, alumbra lithium or potassium, germanate the development or potassium, almogaren lithium or potassium [2]. The essence of this method consists in the dissolution of one of the stable isotopes of samarium, holmium, erbium, dysprosium, rhenium, yttrium in molten at 1500-1600°C glass mass, the shutter speed for the homogenization of the melt, which is then poured on a cold surface or cold water. You get a fine powder of glass, in which a fluidized bed is passed through the flame of an oxygen burner for the formation of spherical particles. Then microparticles are irradiated with neutrons, while stable isotopes become radioactive. The result microspheres labeled153Sm166But,169Er165Dy,186Re,90Y. the Obtained microspheres are washed with acid and again subjected to heat to increase the strength of the microparticles.

The disadvantages of this multi-stage method - technological difficulties associated, first, with the presence of high-temperature processes, and secondly, high-density microspheres, which does not allow them to obtain a stable suspension in a biological solution, which complicates the introduction of them in the body and contributes to the sedimentation of particles in the bloodstream. In addition, you may present undesirable selection in the body of metal ions from the surface of the glass microspheres. An important negative factor is obstacels is in, the activation of isotopes in a nuclear reactor is practically possible only when receiving short-lived isotopes with high value-sectional activation.

The prototype of the claimed invention is a method of producing microspheres of albumin, the essence of which consists in the introduction into the solution of albumin europium salts or lutetium, the emulsification of a mixture of vegetable oil, heated it up to 140-150°C, the allocation of albumin microspheres from the reaction medium, followed by their irradiation in the reactor thermal neutrons [3]. In the stable isotopes151Eu and176Lu activate with the formation of radioactive isotopesMEu and177Lu.

The disadvantages of the prototype are technological complexity (and sometimes impossible) to obtain the product in connection with the limitation of time of irradiation in a nuclear reactor. Prolonged exposure of the protein microspheres dissolved, which does not allow to obtain a product with a high specific activity using stable isotopes with low value-sectional activation.

The technical result of the invention is to obtain microspheres of albumin with high specific activity. This problem can be solved by sorption properties103Pd by entering it into the protein matrix of the ion-exchange method with the subsequent restoration of the fallen is pushing hydrosulfite sodium.

The invention consists in that in the known method, including emulsification solution of albumin in vegetable oil, heat treatment oil emulsions, filtering and neutron activation of stable isotopes in the protein matrix is additionally injected radionuclide103Pd in the form of palladium chloride. Last injected by volume ionoobmennoi sorption. Then103Pd restore hydrosulfite sodium.

Example 1.

1. 5 g of albumin human blood is dissolved in 11.6 ml of distilled water. The resulting solution was dropwise introduced into the reaction vessel containing 900 ml of olive oil with constant stirring speed of 1500 rpm while Continuing the stirring, the mixture is heated to 200-220°C and maintained at this temperature for 2 hours. After that, the suspension of the formed microspheres is filtered off on a glass filter and washed off the oil 4 portions 25 ml diethyl ether, dried at room temperature. Dry microspheres fractionary size on microsite using ultrasonic disintegrator in ethanol, allocate the fraction of particles with a diameter of 20-40 μm and dried at 100°C for 2 hours. The obtained microspheres are kind of brownish powder with a narrow particle size range, obeys the law of Gauss.

30 mg of the obtained microspheres and is of Lumina placed in a beaker of 50 cm 3containing 0.95 to 1.2 mg of palladium chloride in 2 ml of 0.1 M hydrochloric acid, add 1.2 MCI103Pd. The glass mixture is treated with ultrasound to obtain a homogeneous suspension and incubated at room temperature for 24 hours with periodic mixing. Preliminary kinetic experiments showed that the sorption of palladium finishes for 18-20 hours and reaches at 3.3% by weight of the microspheres. Then the microspheres emit by centrifugation and washed three times (10 ml) with 0.1% tween-80 in 0.9% solution of sodium chloride. Of the selected microspheres receive a suspension by mixing 6 ml of 0.1% tween-80 in 0.9%solution of sodium chloride. The resulting suspension103Pd-albumin microspheres (103Pd-MCA-1) brown color used for biological tests on mice.

Example 2.

30 mg of albumin microspheres obtained according to claim 1, placed in a beaker of 50 cm3containing 1.2 mg of palladium chloride in 2 ml of 0.1 M hydrochloric acid, add 1.2 MCI palladium-103. The glass mixture is treated with ultrasound to obtain a homogeneous suspension and incubated at room temperature for 24 hours with periodic mixing. Then the microspheres emit by centrifugation and washed three times (10 ml) with 0.1% tween-80 in 0.9% solution of sodium chloride. Selected microspheres suspension in 0.001 M races is the thief of hydrochloric acid and add 0.3 mg of hydrosulfite sodium (Na 2S2O4for the recovery of palladium and incubated for 24 hours with periodic mixing. Then the microspheres with the recovered palladium allocate by centrifugation and washed three times (10 ml) with 0.1% tween-80 in 0.9% solution of sodium chloride. After that receive a suspension of microspheres with the recovered palladium in 6 ml of 0.1% tween-80. The resulting suspension103Pd-albumin microspheres (103Pd-MCA-2) dark brown color used for biological tests on mice.

From the table it follows that the treatment of the reducing agent after the sorption of palladium greatly slows the rate of elimination of palladium from microspheres (103Pd-MCA-2) compared to the microspheres, in which the palladium has not been repaired (103Pd-MCA-1). The half-life103Pd-MCA-1 from muscle tissue is 24 hours, whereas for103Pd-MCA-1 more than 240 hours.

103Pd-MCA-1
Table
The number of103Pd-MCA-1 and103Pd-MCA-2 in the femoral muscle of mice after intramuscular injection
Time after drug administrationThe residual activity in the muscle of the thigh (% of input)
103Pd-MCA-2
5 min92,499,0
3 hours73,982,6
24 hours47,682,9
72 h20,175,3
120 h14,350,8
240 h5,23a 50.5

The positive effect

The obtained experimental data indicate the feasibility of industrial production of a new dosage form - 103-palladium-albumin microspheres for use in radionuclide therapy of malignant tumors.

Literature

1. Brodack, et al. Radionuclide labelled particles useful for radiation synovectomy. U.S. patent No. 5,320,824 (1994).

2. Day, et al. Composition and method for radiation synovectomy of arthritic joints. U.S. patent No. 5,039,326 (1991).

3. Petries V.M., Stepchenkov VI, Khachirov became popular, Ivanov V.D. Way to obtain microspheres. A.S. No. 673277 (1979).

The method of obtaining labeled with a radionuclide microspheres by emulsification solution of albumin in vegetable oil, heat treatments is Ki emulsion and filtering wherein the stable isotope Pd and radionuclide103Pd in the form of palladium chloride in 0.1 M hydrochloric acid solution is mixed with albumin microspheres, and the resulting mixture is treated with ultrasound to obtain a homogeneous suspension, and then incubated at room temperature for 18-24 h with periodic stirring, then release microspheres from the mixture by centrifugation and restore the palladium hydrosulfite sodium, while using a fraction of microspheres with a diameter of 20-40 μm.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to cardiovascular surgery and can be applied within heart surgical procedures experimentally. For this purpose perfusion is retrograde conducted through aortic cannula with oxygenated solution at first and then with non-oxygenated solution combined with liposome addition under specified conditions. Method provides restoration of contractile function and heart rhythm due to liposomic stabilisation of cell membranes and reduction of lipid peroxidation product.

EFFECT: restoration of contractile function and heart rhythm.

2 cl, 2 ex

FIELD: medicine, pulmonology.

SUBSTANCE: it is necessary to study initial values of functional reserve ability (FRA) of pulmonary-capillary circulation in %, average pressure value in pulmonary artery (AvPPA) in mm mercury column and daily variability of peak volumetric expiration rate (ΔPVRexp.) in % to calculate the following equation: D=+1.376·FRA-2.087·AvPPA-1.023·ΔPVRexp. At D value being above -25.71 one should predict instable flow of bronchial asthma. The innovation enables to carry out integral evaluation of functional state of pulmonary microcirculation, pressure in pulmonary artery and reactivity of respiratory tract.

EFFECT: higher efficiency and accuracy of prediction.

2 ex

FIELD: pharmaceutical chemistry, radioactive nuclide diagnosis and therapy.

SUBSTANCE: claimed method includes sequential mixing under cooling solutions of sodium perrhenate, gelatin, sodium thiosulfate, and hydrochloric acid at sodium thiosulfate and sodium perrhenate molar ratio of 1.5-3.4. Obtained mixture is heated on boiling water bath under continuous stirring for 10 min, cooled, conditioned for 2-3 h, passed through chromatography column filled with anion exchange resin and containing sterilizing filter. Filtrate is collected up to acidic fraction breakthrough, pre-packed at aseptic conditions into sterile bottles for drugs and stored in refrigerator. Said nanocolloid has 80 % or more particles with size of 2-100 nm; 5 % or less particles with size of <20 nm; nanocolloid solution has storage stability of 6 months or more; radioactive preparation obtained on the base of such nanocolloid has radiochemical purity of 90 % or more wherein said radiochemical purity is kept for not less than 4 hours.

EFFECT: new radiopharmaceutical agents useful in lymphoscintigraphy.

3 ex

FIELD: medicine.

SUBSTANCE: method involves determining value of bronchial mucociliar clearance MCC of radiopharmaceutical preparation in % per 1 h, using radioaerosol method. Discriminant equation is to be solved D=-0.6* MCC. D being greater than -15.51, instable bronchial asthma clinical course is to be predicted.

EFFECT: high reliability of prognosis.

FIELD: medicine.

SUBSTANCE: method involves determining value of bronchial mucociliar clearance MCC of radiopharmaceutical preparation in % per 1 h, using radioaerosol method. Discriminant equation is to be solved D=-0.6* MCC. D being greater than -15.51, instable bronchial asthma clinical course is to be predicted.

EFFECT: high reliability of prognosis.

FIELD: pharmaceutical chemistry, radioactive nuclide diagnosis and therapy.

SUBSTANCE: claimed method includes sequential mixing under cooling solutions of sodium perrhenate, gelatin, sodium thiosulfate, and hydrochloric acid at sodium thiosulfate and sodium perrhenate molar ratio of 1.5-3.4. Obtained mixture is heated on boiling water bath under continuous stirring for 10 min, cooled, conditioned for 2-3 h, passed through chromatography column filled with anion exchange resin and containing sterilizing filter. Filtrate is collected up to acidic fraction breakthrough, pre-packed at aseptic conditions into sterile bottles for drugs and stored in refrigerator. Said nanocolloid has 80 % or more particles with size of 2-100 nm; 5 % or less particles with size of <20 nm; nanocolloid solution has storage stability of 6 months or more; radioactive preparation obtained on the base of such nanocolloid has radiochemical purity of 90 % or more wherein said radiochemical purity is kept for not less than 4 hours.

EFFECT: new radiopharmaceutical agents useful in lymphoscintigraphy.

3 ex

FIELD: medicine, pulmonology.

SUBSTANCE: it is necessary to study initial values of functional reserve ability (FRA) of pulmonary-capillary circulation in %, average pressure value in pulmonary artery (AvPPA) in mm mercury column and daily variability of peak volumetric expiration rate (ΔPVRexp.) in % to calculate the following equation: D=+1.376·FRA-2.087·AvPPA-1.023·ΔPVRexp. At D value being above -25.71 one should predict instable flow of bronchial asthma. The innovation enables to carry out integral evaluation of functional state of pulmonary microcirculation, pressure in pulmonary artery and reactivity of respiratory tract.

EFFECT: higher efficiency and accuracy of prediction.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to cardiovascular surgery and can be applied within heart surgical procedures experimentally. For this purpose perfusion is retrograde conducted through aortic cannula with oxygenated solution at first and then with non-oxygenated solution combined with liposome addition under specified conditions. Method provides restoration of contractile function and heart rhythm due to liposomic stabilisation of cell membranes and reduction of lipid peroxidation product.

EFFECT: restoration of contractile function and heart rhythm.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns a way of reception of radioactive microspheres and can be used for reception of radiodrugs for radionuclide therapy of malignant neoplasms. The way of reception labelled a radionuclide of microspheres includes an emulsification of a solution of an albumin in vegetable oil, the further thermal processing of an emulsion and its filtration. Thus stable isotope Pd and a radionuclide 103Pd, in the form of a chloride palladium in 0.1 M a hydrochloric acid solution are admixed with albumin microspheres. The received admixture is processed with ultrasound before reception of homogeneous suspension then it is maintained at a room temperature within 18-24 hours. Microspheres are allocated from an admixture with a centrifugation with the subsequent restoration by Hydrosodium sulfitum. Fraction of microspheres with a diametre 20-40 micron is used.

EFFECT: reception of microspheres of an albumin with high specific activity.

2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a radiopharmaceutical preparation with palladium-103, involving sorption on albumen microspheres of complex palladium-103 chloride with its subsequent reduction with 0.006 n alkaline solution of sodium hydrosulphite Na2S2O4 and washing the product with an ammonium buffer solution.

EFFECT: method reduces loss of palladium-103 during reduction.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to method of obtaining radon-containing concentrate, which lies in barbotage of pure radon or radon with carrier-gas through oil or fat during time necessary for saturation. In the process of barbotage constant volume of carrier-gas is preserved, which is achieved by return of carrier-gas after saturation back into radon source. Invention also relates to device for obtaining radon-containing concentrate, which consists of radon source connected to device for contacting - extractor or bubbler.

EFFECT: inventions make it possible to reduce volume of carrier-gas, reduce time of obtaining concentrate, increase coefficient of radon application.

6 cl, 6 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to product agent of visualisation, which includes radiopharmaceutical composition, supplied in hermetic container. Said radiopharmaceutical composition contains radioisotope, suitable for medical visualisation, presented in biocompatible carrier, in form, suitable for introduction to mammal. Said hermetic container is provided with closure, suitable for puncturing with needle for subcutaneous injections, preserving at the same time seal integrity, and said closure is covered with coating, which includes copolymer of ethylene and tetrafluorethylene (ETFE), on those of its surfaces, which are in contact with container content. Invention also relates to set for preparation of product agent of visualisation, which includes mentioned above hermetic container, which contains non-radioactive precursor, containing reactionable substituent, able to interact with radioisotope source with formation of said pharmaceutical composition. Invention also relates to method of obtaining product agent of visualisation, which includes interaction of precursor mentioned above with radioisotope source in hermetic container.

EFFECT: invention ensures reduction of admixtures in radiopharmaceutical composition due to covering closure with copolymer of ethylene and tetrafluorethylene.

28 cl, 3 tbl, 2 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention relates to method of preparation of inhaled isotope compound, suitable for application in medical diagnostics of patient's state. Claimed method includes electrolytic loading of isotope into carbon crucible by means of electrolysis from isotope solution, which includes free isotope and water-soluble sodium chloride. After that, carried out are sodium chloride sublimation and further isotope ablation in said crucible with formation of ablation aerosol. Obtained aerosol is delivered to patient directly with the purpose of its immediate application by patient. Invention also relates to crucible for application in said method, which is made from high purity graphite and has central part, end contacts and contact legs, crucible walls being made porous and thinner than end contacts and contact legs.

EFFECT: invention ensures reduction of free, non-enclosed into carbon coating radionuclide and reduction of water-soluble sodium chloride concentration.

20 cl, 8 dwg, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical agent to be used as a diagnostic agent containing an inorganic matrix in the form of particles of amorphous or mixed amorphous and crystalline structures which contains a portion of positron emission nuclides in addition to natural isotope distribution of structural type-forming elements anions and cations. The inorganic matrix is represented by topaz (Al2F2)[SiO4], chiolite Na[Al3F4], wavellite Al3(PO4)2(OH, F)2, calcium carbonate CaCO3, maghemite -Fe2O3, zeolites of general formula Mn[(AlO2)x(SiO2)y] (M = metal), magnetic iron Fe3O4, barium sulphate BaSO4, gallium phosphate GaPO4, apatite or fluorohydroxyapatite Ca5(PO4)3(OH, F)=3Ca3(PO4)2*Ca(OH, F)2 and fluorite CaF2. The positron emission nuclides are specified in [15]O, [30]P, [13]N, [65]Ga, [11]C, [131]Ba, [26]A1, [68]Ga and [18]F, and their number in the inorganic matrix makes more than 1. The invention also refers to a method for preparing said pharmaceutical agent involving mixing two solutions of soluble salts and depositing them wherein one salt is saturated by positron emission nuclides, while the cations of one salt are deposited with the cations of the other salt to form the inorganic matrix. The invention also refers to a pharmaceutical composition used for the purpose of diagnostic visualisation wherein more then 0.001% of particles contained in the composition represent said inorganic matrix.

EFFECT: invention provides simplified production of specific particles of the more prolonged applicability for the use which are applicable for diagnostic visualisation.

9 cl, 6 dwg, 2 tbl, 3 ex

Up!