WO2020228558A1 - 放射性颗粒及其制备方法和应用 - Google Patents

放射性颗粒及其制备方法和应用 Download PDF

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WO2020228558A1
WO2020228558A1 PCT/CN2020/088488 CN2020088488W WO2020228558A1 WO 2020228558 A1 WO2020228558 A1 WO 2020228558A1 CN 2020088488 W CN2020088488 W CN 2020088488W WO 2020228558 A1 WO2020228558 A1 WO 2020228558A1
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solution
radionuclide
radioactive
porous
solid carrier
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PCT/CN2020/088488
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English (en)
French (fr)
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陈丽娟
金小卫
蔡起
张家乐
彭亭
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深圳市大西塔科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1248—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles nanotubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the technical field of radiopharmaceutical preparation, and particularly relates to a radioactive particle and a preparation method and application thereof.
  • Tumor radiotherapy is a local treatment method that uses radiation to treat tumors. Its role and position in tumor treatment are increasingly prominent; but radiotherapy generally belongs to "full-line killing", which kills tumors and normal tissues at the same time .
  • Tumor radiotherapy includes external radiation and internal radiation; for some tumors that are far away from the skin tissue and grow in the body, through internal radiation, the radiation directly reaches the tumor tissue, and the normal tissues around the tumor receive a small amount of radiation, which can be obtained Better treatment effect.
  • SIRT Selective Internal Radiation Therapy
  • Radioactive materials are selectively The radiation dose delivered to the tumor tissue is very large, while the amount of radioactive substances in the surrounding normal tissues is small, and the damage to the normal tissues is small.
  • radioactive glass microspheres are based on glass or resin as a matrix loaded with radionuclides such as yttrium (Y)-90, phosphorus (P)-32 and other radioactive microspheres, these radioactive glass microspheres or resin microspheres.
  • radionuclides such as yttrium (Y)-90, phosphorus (P)-32 and other radioactive microspheres
  • Y yttrium
  • P phosphorus
  • radioactive glass microspheres most of the radionuclides loaded on the surface of the radioactive resin microspheres have a small force between the resin microspheres and easily fall off the surface of the resin microspheres and enter the human blood, causing harm to the human body.
  • exchanging radionuclides into the resin and fixing them in the resin by coating methods can easily cause the radionuclide release rate to be high and cannot meet the requirements of treatment.
  • radioactive resin microspheres also have the problem of limited resin exchange capacity and long preparation process.
  • the present invention provides a radioactive particle and its preparation method and application, wherein the preparation method of the radioactive particle is simple and easy to operate, has the advantages of short time-consuming, high radionuclide utilization, green environmental protection and low cost. advantage.
  • the present invention also provides a method for preparing radioactive particles, including:
  • Preparing a first solution the first solution containing at least one cation
  • the second solution contains at least one anion, the cation and/or the anion contains a radionuclide, and the anion can react with the cation to generate a radionuclide precipitate;
  • the porous solid carrier includes a carbon-based material, alumina, At least one of titanium dioxide, diatomaceous earth, attapulgite, zeolite, metal organic framework material and covalent organic framework polymer.
  • the radionuclide in the present invention refers to an unstable atomic nucleus, which can spontaneously emit radiation (such as ⁇ -ray, ⁇ -ray, etc.), and form a stable nuclide through decay.
  • the radionuclide may be a metal radionuclide and/or a non-metal radionuclide.
  • the radionuclide may be a man-made radionuclide or a natural radionuclide.
  • the porous solid supports are all porous materials with stable structure, hydrophilicity and insoluble in water.
  • the carbon-based material may include, but is not limited to, at least one of activated carbon, carbon nanotubes and carbon microspheres.
  • the alumina and titania have stable porous metal oxide particles.
  • the diatomaceous earth is a kind of siliceous rock that contains a small amount of multiple metal oxides (for example, Al 2 O 3 , Fe 2 O 3 , CaO, MgO) and organic matter.
  • the attapulgite is a crystalline hydrated magnesium aluminum silicate mineral.
  • the zeolite is an ore with a framework structure, for example, molecular sieve particles.
  • the metal organic framework materials refer to metal organic framework crystal materials with a periodic network structure formed by organic ligands and metal ions through a self-assembly process.
  • the metal organic framework materials are classified according to the types of organic ligands and include MOFs constructed by nitrogen-containing heterocyclic ligands, MOFs constructed by organic carboxylic acid ligands, and MOFs constructed by nitrogen-containing oxygen mixed ligands.
  • the covalent organic backbone polymers (COFs) are a kind of crystalline microporous polymers.
  • the porous solid carrier further includes at least two of the carbon-based material, alumina, titania, diatomaceous earth, attapulgite, zeolite, metal organic framework material and covalent organic framework polymer.
  • the porous solid carrier includes at least one of diatomaceous earth, attapulgite, and zeolite.
  • the shape of the porous solid support includes one or more of spherical and non-spherical. Further, the shape of the porous solid carrier includes one or more of spherical, quasi-spherical, square, rod-shaped, sheet-shaped and random. For example, in one embodiment of the present invention, the shape of the porous solid support is spherical. In another embodiment of the present invention, the shape of the porous solid support is quasi-spherical.
  • the cation and/or the anion include a radionuclide, including the following three embodiments:
  • both the cations in the first solution and the anions in the second solution contain radionuclides.
  • the cation in the first solution contains a radionuclide
  • the anion in the second solution does not contain a radionuclide
  • the anion in the second solution contains a radionuclide, and the cation in the first solution does not contain a radionuclide.
  • the cation in the first solution contains at least one metal radionuclide.
  • the cation in the first solution may include, but is not limited to, at least one of strontium (Sr-90), yttrium-90 (Y-90), and nickel-63 (Ni-63).
  • the cation is at least one of strontium-90 ion ( 90 Sr 2+ ), yttrium-90 ion ( 90 Y 3+ ), and nickel-63 ion ( 63 Ni 2+ ).
  • the radionuclide contained in the anion in the second solution may include, but is not limited to, at least one of phosphorus-32, sulfur-35, iodine-125, and iodine-131.
  • the acid radical anions include phosphorus-32 (32 PO 4 3-), a sulfur acid radical -35 (35 SO 4 2-), iodine-131 ions (131 I -), and iodine-125 ions (125 I -) At least one of them.
  • the radionuclide-containing cations in the first solution and the radionuclide-containing anions in the second solution may both be derived from corresponding commercially available medical grade radionuclides-containing cations. Vegetarian solution.
  • the anion when the anion does not contain a radionuclide, the anion includes phosphate (PO 4 3- ), carbonate (CO 3 2- ), sulfate (SO 4 2- ), alginate, hydroxide and at least one silicate (SiO 3 2-) - a root (OH).
  • the radionuclide precipitation can be, but not limited to, selected from yttrium phosphate-90 ( 90 YPO 4 ), strontium phosphate-90 ( 90 Sr 3 (PO 4 ) 2 ), nickel carbonate-63 ( 63 NiCO 3 ), At least one of iodine-125 silver (Ag 125 I), iodine-131 silver (Ag 131 I), and calcium phosphorus-32 acid (Ca 3 ( 32 PO 4 ) 2 ).
  • the radionuclide precipitate can also be yttrium-90 ( 90 Y 32 PO 4 ) or strontium-90 ( 90 Sr 3 ( 32 PO 4 ) 2 ).
  • the first solution further includes a non-radioactive metal cation, and the non-radioactive metal cation can react with the anion in the second solution to form a second precipitate;
  • the non-radioactive metal cation includes strontium ion (Sr 2+ ), yttrium ion (Y 3+ ), nickel ion (Ni 2+ ), calcium ion (Ca 2+ ), silver ion (Ag + ) and magnesium ion (Mg 2+ ) one or more Kind.
  • the anion generated by the reaction to generate the second precipitate may or may not include a radionuclide.
  • the second precipitate of the present invention can participate in the adjustment of the radioactive activity of the radionuclide per unit mass of the radioactive particles.
  • the second precipitation can also improve the formation of the radionuclide precipitation to a certain extent by adjusting the concentration of the non-radioactive metal cations and anions forming itself.
  • the second precipitate of the present invention is also stably contained in the porous pores of the porous solid carrier, and the second precipitate and the radionuclide precipitate can mutually enhance the stability of each other in the porous pores.
  • the non-radioactive metal cation in the first solution and the cation in the first solution may be isotopes of each other.
  • the non-radioactive metal cation in the first solution when the cation in the first solution is yttrium-90 ion, the non-radioactive metal cation is yttrium-89 ion.
  • the non-radioactive metal cation when the cation in the first solution is nickel-63 ion, the non-radioactive metal cation is nickel-58 ion.
  • the metal cation may be selected from at least one of calcium ion, magnesium ion and silver ion.
  • the first solution and the second solution are both solutions without precipitation and suspended particles.
  • the first solution includes a first soluble salt
  • the first soluble salt includes a cation containing a radionuclide.
  • the anion of the first soluble salt may, but is not limited to, a halogen ion, such as chloride ion.
  • the second solution includes a second soluble salt
  • the cation in the second soluble salt may be, but is not limited to, sodium ion and/or potassium ion.
  • the anion of the second soluble salt includes at least one of phosphate, carbonate, sulfate, alginate, hydroxide, and silicate .
  • the second soluble salt includes sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium sulfate, potassium sulfate, sodium hydroxide, sodium alginate ((C 6 H 7 O 6 Na) n ) and sodium silicate One or more of.
  • the first solution further includes a third soluble salt, and the third soluble salt includes a non-radioactive metal cation; the anion in the third soluble salt may but is not limited to a halogen ion; for example, a chloride ion.
  • the anion in the third soluble salt and the anion in the first soluble salt may be the same or different.
  • the anion in the third soluble salt is the same as the anion in the first soluble salt.
  • the anions in the first solution are derived from the anions of the first soluble salt and the third soluble salt.
  • the cation in the first solution when the anion in the second solution contains a radionuclide, the cation in the first solution is excessive relative to the anion in the second solution; The cations in the first solution can completely precipitate the anions in the second solution.
  • the second solution may also include non-radioactive anions, and the cations in the first solution may also completely precipitate the second The non-radioactive anion in solution.
  • the anion in the second solution is 32 PO 4 3-
  • the second solution may also contain PO 4 3-
  • the first solution may contain a large amount of Ca 2+
  • the first solution Ca 2+ in one solution can completely precipitate 32 PO 4 3- and PO 4 3- in the second solution.
  • the non-radioactive anion in the second solution may be an anion dissolved in a fourth soluble salt in the second solution, and the non-radioactive anion may be phosphate, carbonate, sulfate, or alginate. , At least one of hydroxide and silicate.
  • the porous pores of the porous solid carrier also contain water and soluble metal salts, and the soluble metal salts include sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium sulfate, potassium sulfate, sodium carbonate, One or more of potassium carbonate, sodium alginate, potassium alginate, sodium silicate, and potassium silicate.
  • the soluble metal salt includes the unreacted second soluble salt, and the soluble secondary salt generated by the reaction between the second solution and the first solution.
  • the soluble secondary salt generated by the reaction between the second solution and the first solution refers to the salt formed by the anion in the first solution and the cation in the second solution.
  • the salt formed by the anion in the first solution and the cation in the second solution may include, but is not limited to, at least one of sodium chloride and potassium chloride.
  • the process of collecting radioactive particles may be directly collecting the radioactive particles.
  • the process of collecting radioactive particles may also be indirectly collecting the radioactive particles.
  • the radioactive particles are collected after deionized cleaning, filtration, and drying steps.
  • the water and soluble metal salt in the porous pores in the radioactive particles collected after washing with deionized water, filtering, and drying can be removed.
  • the radioactive particles are collected after washing with deionized water, filtration, and drying, and the porous pores of the radioactive particles only contain the radionuclide precipitate and the second precipitate.
  • the radioactive particles when the soluble metal salt in the porous pores of the radioactive particles has no additional harmful side effects to the human body, the radioactive particles can be directly collected.
  • the soluble metal salt may be, but is not limited to, sodium chloride, potassium chloride, or phosphate, or the amount of the soluble metal salt is extremely small and not enough to cause harm to the human body.
  • the pH range of the first solution is 6.0-8.0. Further, the pH range of the first solution is 6.5-7.5.
  • the pH range of the second solution is 6.0-12.0. Further, the pH range of the second solution is 6.5-10.
  • the total volume of the first solution and the second solution is less than or equal to the total water absorption of the porous solid carrier.
  • the total volume of the first solution and the second solution is less than the total water absorption of the porous solid carrier.
  • the porous solid carrier is a hydrophilic material with porous pores and is insoluble in water.
  • the porous solid carrier also has a certain amount of water absorption. That is, the porous solid carrier can absorb a certain amount of aqueous solution.
  • the water absorption of the porous solid carrier of different materials may vary.
  • the total water absorption of the porous solid carrier refers to the maximum water absorption volume per unit mass of the porous solid carrier maintaining the powdery (or monodispersed state) under normal temperature and pressure.
  • the unit of water absorption of the porous solid carrier can be expressed in a volume unit, for example, mL.
  • the total water absorption of the porous solid carrier can also be obtained by converting the mass of the porous solid carrier and the water absorption of the porous solid carrier.
  • the water absorption of the porous solid carrier in the present invention refers to the ratio (%) of the mass of the largest aqueous solution that the porous solid carrier maintains powdery absorption to the dry weight of the porous solid carrier.
  • the first solution and the second solution are less than or equal to the total water absorption of the certain amount of porous solid carrier, in the preparation process of radioactive particles, the first solution and the The second solution will all enter the porous pores of the porous solid carrier, and the prepared radioactive particles are in a dispersed powder form.
  • the volume of the first solution or the second solution can be adjusted according to the concentration of the solute in the respective solution; in order to realize that the anions in the second solution can be completely precipitated out of the first solution.
  • the cation containing the radionuclide or the cation of the first solution can completely precipitate the anion containing the radionuclide in the second solution.
  • the volume ratio of the first solution to the second solution is 1: (0.1-10).
  • the volume ratio of the first solution to the second solution is 1: (0.5-2).
  • the volume ratio of the first solution to the second solution is 1:1.
  • the porous solid carrier is fully stirred.
  • the stirring speed of the full stirring process may be 60-100 revolutions per minute, and the stirring time may be 1-10 minutes.
  • the porous solid carrier to which the first solution and the second solution have been added dropwise is fully stirred.
  • the stirring speed of the full stirring process may be 60-100 revolutions per minute, and the stirring time may be 1-10 minutes.
  • the second solution By fully stirring the porous solid carrier to which the first solution and the second solution have been added dropwise, the second solution can be dispersed more uniformly, and the second solution can enter the In the porous pores of the porous solid carrier; more importantly, it can promote the anion in the second solution and the cation containing the metal radionuclide to more fully form a radionuclide precipitation.
  • the particle size of the porous solid carrier is 0.05 ⁇ m-600 ⁇ m.
  • the particle size of the porous solid carrier is 0.05 ⁇ m-600 ⁇ m.
  • the particle size of the porous solid carrier is 10 ⁇ m-500 ⁇ m.
  • the particle size of the porous solid carrier is 10 ⁇ m-300 ⁇ m.
  • the particle size of the porous solid carrier is 10 ⁇ m-100 ⁇ m.
  • the particle size of the porous solid carrier is 30 ⁇ m-80 ⁇ m.
  • the porous pore size of the porous solid support is 0.1 nm to 600 nm.
  • the porous solid support has a porous pore size of 0.1 nm-50 nm.
  • the porous pore size of the porous solid support is 0.1 nm-20 nm.
  • the porous pore size of the porous solid carrier is nanometer-sized and very small, and the radionuclide precipitate can be embedded in the porous pores of the porous solid carrier, and the structure is stable. After testing, the radionuclide release rate of the radioactive particles of the present invention is extremely low, and the radionuclide hardly separates from the porous solid carrier.
  • the porous solid carrier can pass through a particle size screening process before being used to prepare the radioactive particles.
  • the particle size screening process can be passed through a conventional screening device, for example, a classification device such as a screen with a certain aperture.
  • the preparation method of the radioactive particles developed by the present invention is simpler and easier to operate; and the entire preparation process takes extremely short time, and is especially suitable for preparing radioactive particles of metal radionuclides with a short half-life.
  • the preparation method of the invention is environmentally friendly and has low cost.
  • the present invention provides a radioactive particle comprising a porous solid carrier and at least one radionuclide precipitate contained in the porous pores of the porous solid carrier;
  • the porous solid carrier is hydrophilic, so The radionuclide precipitation is generated by the reaction of cations and anions, and the cations and/or the anions include radionuclides;
  • the porous solid support includes carbon-based materials, alumina particles, titanium dioxide, diatomaceous earth, attapulgite, At least one of zeolite, metal organic framework material and covalent organic framework polymer.
  • the cation and/or the anion include a radionuclide, including the following three embodiments:
  • the radionuclide precipitate is generated by the reaction of a cation and an anion, the cation contains a radionuclide, and the anion does not contain a radionuclide.
  • the radionuclide precipitate is generated by the reaction of a cation and an anion, the anion contains a radionuclide, and the cation does not contain a radionuclide.
  • the radionuclide precipitate is generated by the reaction of cations and anions, and both the cations and anions contain radionuclides.
  • the cation contains at least one of metal radionuclides.
  • the radionuclide contained in the cation may include, but is not limited to, at least one of strontium, yttrium-90, and nickel-63.
  • the cation is at least one of strontium-90 ion, yttrium-90 ion and nickel-63 ion.
  • the anion includes at least one of non-metallic radionuclides.
  • the radionuclide contained in the anion may include, but is not limited to, at least one of phosphorus-32, sulfur-35, iodine-131, and iodine-125.
  • the anion includes at least one of phosphorus-32 acid radical, sulfur-35 acid radical, iodine-131 ion, and iodine-125 ion.
  • the anion when the anion does not include the radionuclide, includes at least one of phosphate, carbonate, sulfate, alginate, hydroxide, and silicate.
  • the radionuclide precipitation may be at least selected from the group consisting of yttrium phosphate-90, strontium phosphate-90, nickel carbonate-63, iodine-125 silver, iodine-131 silver and calcium phosphorus-32 acid One kind.
  • the radionuclide precipitate can also be yttrium-90 phosphorous-32 acid or strontium-phosphorus-32 acid-90.
  • the radionuclide precipitation refers to a solid substance that is hardly soluble in water, and almost no radionuclide-containing cations or anions are released in an aqueous solution.
  • the radionuclide precipitate of the present invention is stably contained in the porous pores of the porous solid carrier, has a wide application range for temperature and pH, and is very stable in the temperature and pH range of the human body.
  • the radionuclide deposits contained in the porous holes can be one type, or two or more types of radionuclide deposits.
  • Each of the radionuclide precipitates may contain one type of radionuclide or two or more types of radionuclide.
  • the radionuclide precipitation is a radionuclide precipitation containing Sr-90, a radionuclide containing Y-90 or a radionuclide containing Ni-63; another of the present invention
  • the porous hole contains two kinds of radionuclide precipitates, one of which contains Y-90 in the radionuclide precipitate; the other contains Sr-90 in the radionuclide precipitate; in other embodiments, the The radionuclide precipitate may contain two radionuclides at the same time, for example, the radionuclide precipitate contains Sr-90 and Y-90 at the same time.
  • the radionuclide precipitation may be, but not limited to, at least one selected from the group consisting of yttrium phosphate-90, strontium phosphate-90, and nickel carbonate-63.
  • the shape of the radioactive particles includes one or more of spherical and non-spherical. Further, the shape of the radioactive particles includes one or more of spherical, quasi-spherical, square, rod-like, flake-like and irregular shapes. For example, in one embodiment of the present invention, the shape of the radioactive particles is spherical.
  • the porous solid carrier further includes a second precipitate in the porous pores, and the second precipitate is generated by the reaction of a non-radioactive metal cation and the anion, and the non-radioactive metal cation includes strontium ion and yttrium ion , One or more of nickel ion, calcium ion, silver ion and magnesium ion.
  • the anion that reacts with the non-radioactive metal cation to form the second precipitate may or may not include a radionuclide.
  • the anion when the anion does not contain the radionuclide, the anion includes at least one of phosphate, carbonate, sulfate, alginate, hydroxide, and silicate.
  • the radionuclide included in the anion may include, but is not limited to, at least one of phosphorus-32, sulfur-35, iodine-125, and iodine-131.
  • the non-radioactive metal cation and the cation that reacted to generate the radioactive precipitate may be isotopes of each other.
  • the non-radioactive metal cation when the cation that reacts to generate the radionuclide precipitate is yttrium-90 ion, the non-radioactive metal cation is yttrium 89 ion.
  • the non-radioactive metal cation when the cation that reacts to generate the radionuclide precipitate is nickel-63 ion, the non-radioactive metal cation is nickel 58 ion.
  • the non-radioactive metal cation may be selected from at least one of calcium ion, magnesium ion and silver ion.
  • the porous solid support also includes water and soluble metal salts in the porous pores, and the soluble metal salts include sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium sulfate, potassium sulfate, and carbonate.
  • the soluble metal salts include sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium sulfate, potassium sulfate, and carbonate.
  • sodium, potassium carbonate, sodium alginate, potassium alginate, sodium silicate and potassium silicate are examples of sodium, potassium carbonate, sodium alginate, potassium alginate, sodium silicate and potassium silicate.
  • the porous pore size of the porous solid support is 0.1 nm to 600 nm.
  • the porous solid support has a porous pore size of 0.1 nm-50 nm.
  • the porous pore size of the porous solid support is 0.1 nm-20 nm.
  • the porous pore size of the porous solid carrier is nanometer-sized and very small, and the radionuclide precipitate can be embedded in the porous pores of the porous solid carrier, and the structure is stable. After testing, the radionuclide release rate of the radioactive particles of the present invention is extremely low, and the radionuclide hardly separates from the porous solid carrier.
  • the particle size of the porous solid carrier is 0.05 ⁇ m-600 ⁇ m.
  • the particle size of the porous solid carrier is 10 ⁇ m-500 ⁇ m.
  • the particle size of the porous solid carrier is 10 ⁇ m-300 ⁇ m.
  • the particle size of the porous solid carrier is 10 ⁇ m-100 ⁇ m.
  • the particle size of the porous solid carrier is 30 ⁇ m-80 ⁇ m.
  • the particle size of the porous solid carrier is 30 ⁇ m-60 ⁇ m.
  • the particle size of the porous solid support particles may be, but not limited to, 30 ⁇ m, or 35 ⁇ m, or 40 ⁇ m, or 45 ⁇ m, or 50 ⁇ m, or 55 ⁇ m, or 60 ⁇ m.
  • the mass of the radionuclide precipitation in the porous pores of the porous solid carrier per unit mass can be adjusted according to actual needs.
  • the radioactivity of the radionuclide in the radioactive particles can also be adjusted according to actual needs.
  • the radioactivity of the radionuclide per gram of the radioactive particles is 0.1GBq-50GBq. Further, optionally, the radioactivity of the radionuclide per gram of the radioactive particles is 0.1 GBq-30 GBq.
  • the radioactive particles of the second aspect of the present invention are prepared by the preparation method of the first aspect of the present invention.
  • the present invention also provides an application of the radioactive particles prepared by the preparation method according to the first aspect of the present invention in the preparation of drugs for treating tumors.
  • the radioactive particles of the present invention have the characteristics of stable structure, low release rate of radionuclides, high safety and low cost, the radioactive particles of the present invention have broad application prospects in the field of preparing drugs for treating tumors. .
  • the present invention also provides a preparation for radiotherapy, including the radioactive particles and pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipient in the present invention refers to an adjuvant that does not cause side effects.
  • the excipient may include, but is not limited to, diluents, binders, fillers, coating polymers, plasticizers, glidants, disintegrants, lubricants, and release rate regulators.
  • the excipient may be physiological saline. Because the radioactive particles of the present invention are hydrophilic; therefore, the radioactive particles can be uniformly distributed in the physiological saline.
  • the radioactive particles of the present invention may contain at least one radionuclide, and the radioactive activity of the radioactive particles can be controlled by adjusting and controlling the precipitation content of the radionuclide; and the structure of the radioactive particles is stable, and the release rate of the radionuclide Low, with a particle size range of 0.05-600 ⁇ m; can be used to prepare most medical radiotherapy preparations; the preparation can be widely used in radiotherapy drugs for the treatment of various tumors and other diseases.
  • the preparation can reach the tumor site by perfusion, and the radionuclide precipitates in the porous pores of the radioactive particles contained in the preparation can emit beta rays to kill the tumor and achieve the purpose of treatment;
  • the preparation for radiotherapy can also effectively control tumor invasion and metastasis, and has a strong killing effect on tumor cells, but has very low damage to normal cells around the tumor.
  • the preparation of the present invention can be used in radiotherapy of liver cancer by arterial perfusion embolization, and can also be used in radiotherapy of other malignant tumors, such as breast cancer, lung cancer, kidney cancer or tongue cancer.
  • the preparation method of the radioactive particles of the present invention is simple and easy to operate, and the entire preparation process takes very short time, and can be used to prepare radioactive particles containing radionuclides with a short half-life; the radioactivity in the preparation method of the present invention
  • the nuclide utilization rate is extremely high, environmental protection, low cost, and can be applied to industrialized mass production.
  • the radioactive particles of the present invention include a porous solid carrier and at least one radionuclide precipitate contained in the porous pores of the porous solid carrier; the structure of the radioactive particles is stable, the radionuclide release rate is low, and the The particle size of the radioactive particles, the type of radionuclide in the radionuclide precipitation and the radioactivity can be adjusted, the safety is high, and the application prospect is broad.
  • the radioactive particles of the present invention have broad application prospects in the field of preparing drugs for the treatment of tumors. They have the characteristics of high safety and low cost.
  • the radioactivity and particle size of the radioactive particles can be It can be adjusted according to actual needs and can be used for radiotherapy preparations for a variety of malignant tumors.
  • Figure 1 is a schematic flow chart of a method for preparing radioactive particles in an embodiment of the present invention.
  • the chemical reagents used in the preparation method are all commercially available reagents.
  • Figure 1 is a schematic flow chart of a method for preparing radioactive particles according to an embodiment of the present invention, including the following steps:
  • the first solution and/or the second solution may be prepared before the preparation.
  • the half-life of the radionuclide is very short, it can be temporarily configured during the preparation process.
  • the control group 1 in this embodiment is strictly implemented according to the steps of the preparation method of the radioactive particles of the present invention. The difference is that the radionuclide Y-90 solution is replaced with its non-radioactive stable isotope Y-89 solution. It is to facilitate the detection of ion concentration and reduce the damage of radionuclides to detection personnel and equipment.
  • the particle size of the porous solid carrier is about 50 ⁇ m.
  • the total water absorption of the porous solid carrier is about 20mL.
  • a method for preparing radioactive particles containing yttrium-90 includes:
  • the particle size of the porous activated carbon particles is about 50 ⁇ m.
  • the total water absorption of the porous activated carbon particles is about 20 mL.
  • Example 1 In the preparation process of Example 1, the second solution was prepared in advance, the preparation of the first solution started timing, and it took about 35 minutes to finally receive the radioactive particles containing yttrium-90. Weigh out 1g of prepared radioactive particles containing yttrium-90, and test with a radioactivity meter. The measured activity of 1g of radioactive particles is 0.25GBq. And by characterizing the prepared radioactive particles and the porous activated carbon particles used, it can be found that there is no significant difference in the surface morphology of the radioactive particles and porous activated carbon particles.
  • a method for preparing radioactive particles containing yttrium-90 includes:
  • Example 2 In the preparation process of Example 2, the second solution was prepared in advance, the preparation of the first solution started timing, and it took about 40 minutes to finally receive the radioactive particles containing yttrium-90. Weigh out 1g of prepared radioactive particles containing yttrium-90, and test them with a radioactivity meter. The measured activity of 1g of radioactive particles is 0.44GBq.
  • a method for preparing radioactive particles containing yttrium-90 includes:
  • the particle size of the porous activated carbon particles is about 30 ⁇ m.
  • the total water absorption of the porous activated carbon particles is about 50 mL.
  • Example 3 In the preparation process of Example 3, the second solution was prepared in advance, the preparation of the first solution started timing, and it took about 44 minutes to finally receive the radioactive particles containing yttrium-90. Weigh out 1g of prepared radioactive particles containing yttrium-90 and test with a radioactivity meter. The measured activity of 1g of radioactive particles is 0.50GBq.
  • a method for preparing radioactive particles containing yttrium-90 includes:
  • the particle size of the porous activated carbon particles is about 30 ⁇ m.
  • the total water absorption of the porous activated carbon particles is about 50 mL.
  • Example 4 In the preparation process of Example 4, the second solution was prepared in advance, the preparation of the first solution started timing, and it took about 40 minutes to finally receive the radioactive particles containing yttrium-90. Weigh out 1g of prepared radioactive particles containing yttrium-90 and test with a radioactivity meter. The measured activity of 1g of radioactive particles is 0.50GBq.
  • a preparation method of strontium-90-containing radioactive particles includes:
  • the particle size of the porous activated carbon particles is about 50 ⁇ m.
  • the total water absorption of the porous activated carbon particles is about 20 mL.
  • Example 5 In the preparation process of Example 5, the second solution was prepared in advance, the preparation of the first solution started timing, and it took about 35 minutes to finally receive the radioactive particles containing strontium-90. Weigh out 1g of prepared radioactive particles containing strontium-90, and test with a radioactivity meter. The measured activity of 1g of radioactive particles is 0.40GBq.
  • a method for preparing radioactive particles containing nickel-63 including:
  • Example 5 In the preparation process of Example 5, the second solution was prepared in advance, the preparation of the first solution started timing, and it took about 35 minutes to finally receive the radioactive particles containing nickel-63. Weigh 1g of the prepared radioactive particles containing nickel-63, and test with a radioactivity meter. The measured activity of 1g of radioactive particles is 0.40GBq.
  • a preparation method of phosphorus-32-containing radioactive particles including:
  • the particle size of the porous activated carbon particles is about 50 ⁇ m.
  • the total water absorption of the porous activated carbon particles is about 20 mL.
  • Example 7 In the preparation process of Example 7, the second solution was prepared in advance, the preparation of the first solution started timing, and it took about 35 minutes to finally receive the radioactive particles containing phosphorus-32. Weigh out 1g of prepared radioactive particles containing phosphorus-32 and test with a radioactivity meter. The measured radioactivity of 1g of radioactive particles is 0.25GBq.
  • a method for preparing radioactive particles containing iodine-125 including:
  • the particle size of the porous activated carbon particles is about 50 ⁇ m.
  • the total water absorption of the porous activated carbon particles is about 20 mL.
  • Example 8 In the preparation process of Example 8, the second solution was prepared in advance, the preparation of the first solution started timing, and it took about 35 minutes to finally receive radioactive particles containing iodine-125. Weigh out 1g of prepared radioactive particles containing iodine-125 and test with a radioactivity meter. The measured activity of 1g of radioactive particles is 0.25GBq.
  • Experimental group 3 0 Experimental group 4 0 Experimental group 5 0 Experimental group 6 0 Experimental group 7 0 Experimental group 8 0
  • the radioactive particles prepared in Examples 1-8 of the present invention all show good structural stability. After long-term immersion, the radioactivity is detected, and the release rate of radionuclides is close to 0. %, indicating that the radionuclide in the radioactive particles worthy of the preparation method of the present invention will not leak risk.
  • non-radioactive particles containing yttrium 89 were prepared by the preparation method described in control group 1, and 20 mL of 10% physiological saline was added and sealed. Then it was placed in a 50°C thermostat, taken out and shaken for 5 minutes every day, and left for 14 days. After 14 days, the filtrate was collected by centrifugation, and the concentration of yttrium ion in the filtrate was measured by ICP (inductively coupled plasma spectrometer).
  • the ICP test results show that the yttrium ion concentration in the filtrate is less than 0.02mg/L (below the detection limit, that is, no yttrium ion is detected).
  • the ICP test results showed that the yttrium ion concentration in the filtrate was 40 ppm.

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Abstract

本发明提供一种放射性颗粒的制备方法，配制第一溶液和第二溶液，所述第一溶液中含有至少一种阳离子；所述第二溶液中含有至少一种阴离子，所述阳离子和/或所述阴离子包含放射性核素；取一定量亲水性的多孔固体载体，先后将所述第一溶液和所述第二溶液缓慢滴加至所述多孔固体载体中，所述第二溶液中的阴离子与所述第一溶液中的金属阳离子在所述多孔孔洞内反应生成所述放射性核素沉淀，然后收集得到放射性颗粒；所述多孔固体载体包括碳基材料、氧化铝颗粒、二氧化钛、硅藻土、凹凸棒土、沸石、金属有机框架材料和共价有机骨架聚合物中的至少一种。该制备方法简单易操作，耗时短和成本低。本发明还提供了放射性颗粒及其在治疗肿瘤的药物上的应用。

Description

放射性颗粒及其制备方法和应用
本申请要求了2019年05月13日提交中国专利局的，申请号201910394215.9，发明名称为“放射性颗粒及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于放射性药物制备技术领域，尤其涉及一种放射性颗粒及其制备方法和应用。
背景技术
恶性肿瘤具有发病率高，死亡率高等特点，是目前严重威胁人们生命安全的重大疾病之一。肿瘤放射治疗(放疗)是利用放射线治疗肿瘤的一种局部治疗方法，其在肿瘤治疗中的作用和地位日益突出；但是放疗一般属于“全线杀伤”，在杀伤肿瘤的同时，也杀伤了正常组织。肿瘤放射治疗包括体外照射和体内照射方式；对于一些距离皮肤组织比较远、生长在体内的肿瘤，通过体内照射，射线直接到达肿瘤组织，而肿瘤周围的正常组织受照射量很小，这样可以获得更佳的治疗效果。例如，近来发展的选择性内照射治疗(Selective Internal Radiation Therapy,SIRT)技术，就是将含有放射性同位素的药物注入体内或将器械贴近或插入到靶组织进行放射治疗，放射性物质是被有选择性地输送到肿瘤组织中，对肿瘤组织的辐射剂量很大，而周围正常组织中进入的放射性物质的量很少，对正常组织的损害很小。
然而现有的含有放射性同位素的药物大部分是以玻璃或树脂为基体负载如钇(Y)-90、磷(P)-32等放射性核素的放射性微球，这些放射性玻璃微球或树脂微球都存在一些不足。例如，放射性玻璃微球中的玻璃密度较高(2.0cm/g-2.7cm/g)，需要用甘油导入至肿瘤部位，会影响治疗效果；同时，放射性玻璃微球必须用反应堆进行辐照，但玻璃原料中的杂质经过中子辐照后，会产生释放γ射线的核素，使患者遭受不必要的放射性损伤；而且放射性玻璃微球的制备过程复杂，反应条件苛刻。而对于放射性树脂微球，大部分负载在放射性树脂微球表面的放射性核素与树脂微球之间的作用力小，容易从树脂微球表面脱落进入人体血液，对人体产生危害。而将放射性核素交换至树脂内部，并用包被的方法固定在树脂内部，也容易造成放射性核素释放率高无法满足治疗的要求。此外，放射性树脂微球也存在树脂的交换容量有限，制备过程耗时长的问题。
因此，开发一种结构安全稳定、方便实用，且制备过程简单高效的放射性颗粒对于肿瘤放射治疗具有重要意义。
发明内容
为解决上述问题，本发明提供了一种放射性颗粒及其制备方法和应用，其中，该放射性颗粒的制备方法简单易操作，具有耗时短、放射性核素利用率高、绿色环保和成本低等优点。
第一方面，本发明还提供了一种放射性颗粒的制备方法，包括：
配制第一溶液，所述第一溶液中含有至少一种阳离子；
配制第二溶液，所述第二溶液中含有至少一种阴离子，所述阳离子和/或所述阴离子包含放射性核素，所述阴离子能与所述阳离子反应生成放射性核素沉淀；
取一定量亲水性的多孔固体载体，先将所述第一溶液缓慢滴加至所述多孔固体载体中，并充分搅拌使所述第一溶液进入所述多孔固体载体的多孔孔洞内；再将所述第二溶液缓慢滴加至所述多孔固体载体中，搅拌使所述第二溶液进入所述多孔孔洞内，所述第二溶液中的阴 离子与所述第一溶液中的金属阳离子在所述多孔孔洞内反应生成所述放射性核素沉淀，所述放射性核素沉淀容置于所述多孔孔洞内，然后收集得到放射性颗粒；其中，所述多孔固体载体包括碳基材料、氧化铝、二氧化钛、硅藻土、凹凸棒土、沸石、金属有机框架材料和共价有机骨架聚合物中的至少一种。
其中，本发明所述放射性核素是指不稳定的原子核，能自发地放出射线(如α射线、β射线等)，通过衰变形成稳定的核素。所述放射性核素可以为金属放射性核素和/或非金属放射性核素。所述放射性核素可以为人造放射性核素或天然放射性核素。
本发明中，所述多孔固体载体均为结构稳定、具有亲水性且不溶于水的多孔材料。其中，所述碳基材料可以但不限于包括活性炭、碳纳米管和碳微球中至少一种。
所述氧化铝、二氧化钛具有稳定的多孔金属氧化物颗粒。所述硅藻土是一种硅质岩石，包含有少量且多种的金属氧化物(例如Al 2O 3、Fe 2O 3、CaO、MgO)和有机质。所述凹凸棒土为一种晶质水合镁铝硅酸盐矿物。所述沸石是一种具有架状结构的矿石，例如可以是分子筛颗粒。
所述金属有机框架材料(MOFs)是指有机配体与金属离子通过自组装过程形成的具有周期性网络结构的金属有机骨架晶体材料。本发明中，所述金属有机框架材料根据有机配体的种类划分包括含氮杂环类配体构筑的MOFs、有机羧酸类配体构筑的MOFs、含氮氧混合类配体构筑的MOFs。所述共价有机骨架聚合物(COFs)为一种结晶微孔聚合物。
可选地，所述多孔固体载体还包括所述碳基材料、氧化铝、二氧化钛、硅藻土、凹凸棒土、沸石、金属有机框架材料和共价有机骨架聚合物中的至少两种。
进一步地，可选地，所述多孔固体载体包括硅藻土、凹凸棒土和沸石中的至少一种。
本发明中，所述多孔固体载体的形状包括球形和非球形中的一种或多种。进一步地，所述多孔固体载体的形状包括球形、类球形、方形、棒状形、片状形和无规则形中的一种或多种。例如，本发明一实施方式中，所述多孔固体载体的形状为球形。本发明另一实施方式中，所述多孔固体载体的形状为类球形。
本发明中，所述阳离子和/或所述阴离子包含放射性核素，包括以下三种实施方式：
本发明第一实施方式中，所述第一溶液中的所述阳离子和所述第二溶液中的所述阴离子都包含放射性核素。
本发明第二实施方式中，所述第一溶液中的所述阳离子包含放射性核素，所述第二溶液中的所述阴离子不含放射性核素。
本发明第三实施方式中，所述第二溶液中的所述阴离子包含放射性核素，所述第一溶液中的所述阳离子不含放射性核素。
可选地，所述第一溶液中的所述阳离子包含至少一种金属放射性核素。
可选地，所述第一溶液中的所述阳离子可以但不限于包括锶(Sr-90)、钇-90(Y-90)和镍-63(Ni-63)中的至少一种。例如，所述阳离子为锶-90离子( 90Sr 2+)、钇-90离子( 90Y 3+)和镍-63离子( 63Ni 2+)中的至少一种。
可选地，所述第二溶液中的所述阴离子中包含的放射性核素可以但不限于包括磷-32，硫-35和碘-125、碘-131中的至少一种。例如，所述阴离子包括磷-32酸根( 32PO 4 3-)，硫-35酸根( 35SO 4 2-)、碘-131离子( 131I -)、和碘-125离子( 125I -)中的至少一种。
本发明中，所述第一溶液中的所述包含放射性核素的阳离子和所述第二溶液中的所述包含放射性核素的阴离子均可以是来源于对应的市售医用级的含放射性核素的溶液。
进一步地，当所述阴离子不包含放射性核素时，所述阴离子包括磷酸根(PO 4 3-)、碳酸根(CO 3 2-)、硫酸根(SO 4 2-)、海藻酸根、氢氧根(OH -)和硅酸根(SiO 3 2-)中的至少一种。
具体地，所述放射性核素沉淀可以但不限于选自磷酸钇-90( 90YPO 4)、磷酸锶-90( 90Sr 3(PO 4) 2)、碳酸镍-63( 63NiCO 3)、碘-125化银(Ag 125I)、碘-131化银(Ag 131I)和磷-32酸钙(Ca 3( 32PO 4) 2)中的至少一种。
例如，所述放射性核素沉淀还可为磷-32酸钇-90( 90Y 32PO 4)或磷-32酸锶-90( 90Sr 3( 32PO 4) 2)。
可选地，所述第一溶液中还包括非放射性金属阳离子，所述非放射性金属阳离子能与所述第二溶液中的所述阴离子反应生成第二沉淀；所述非放射性金属阳离子包括锶离子(Sr 2+)、钇离子(Y 3+)、镍离子(Ni 2+)、钙离子(Ca 2+)、银离子(Ag +)和镁离子(Mg 2+)中的一种或多种。
可选地，反应生成所述第二沉淀的所述阴离子可以包括放射性核素，也可以不包括放射性核素。
本发明所述第二沉淀一方面可以参与调节单位质量的所述放射性颗粒中的放射性核素的放射性活动大小。所述第二沉淀另一方面还可以通过调节形成自身的非放射性金属阳离子和阴离子的浓度一定程度地改善所述放射性核素沉淀的形成。本发明所述第二沉淀同样是稳定地容置在多孔固体载体的多孔孔洞内，所述第二沉淀和所述放射性核素沉淀可以相互增强彼此在所述多孔孔洞内的稳固性。
进一步地，可选地，所述第一溶液中的所述非放射性金属阳离子与所述第一溶液中的所述阳离子可以互为同位素。例如，本发明一实施方式中，所述第一溶液中的所述阳离子为钇-90离子时，所述非放射性金属阳离子为钇-89离子。本发明另一实施方式，所述第一溶液中的所述阳离子为镍-63离子时，所述非放射性金属阳离子为镍-58离子。
可选地，当所述含放射性核素的阳离子没有对应的稳定同位素时，所述金属阳离子可以选自钙离子、镁离子和银离子中的至少一种。
本发明中，所述第一溶液和第二溶液均为无沉淀、无悬浮颗粒的溶液。例如，本发明一实施方式中，所述第一溶液包含有第一可溶性盐，所述第一可溶性盐包括含放射性核素的阳离子。所述第一可溶性盐的阴离子可以但不限于为卤素离子，例如氯离子。
本发明一实施方式中，所述第二溶液包括第二可溶性盐，所述第二可溶性盐中的阳离子可以但不限于为钠离子和/或钾离子。当所述第二可溶性盐的阴离子不含放射性核素时，所述第二可溶性盐的所述阴离子包括磷酸根、碳酸根、硫酸根、海藻酸根、氢氧根和硅酸根中的至少一种。例如，所述第二可溶性盐包括磷酸钠、磷酸钾、碳酸钠、碳酸钾、硫酸钠、硫酸钾、氢氧化钠、海藻酸钠((C 6H 7O 6Na) n)和硅酸钠中的一种或多种。
进一步地，所述第一溶液还包括第三可溶性盐，所述第三可溶性盐包括非放射性金属阳离子；所述第三可溶性盐中的阴离子可以但不限为卤素离子；例如氯离子。
进一步地，可选地，所述第三可溶性盐中的阴离子与所述第一可溶性盐的阴离子可以相同也可以不同。例如，本发明一实施方式中，所述第三可溶性盐中的阴离子与所述第一可溶性盐的阴离子相同。所述第一溶液中的阴离子来源于所述第一可溶性盐和所述第三可溶性盐的阴离子。
本发明所述制备方法中，当第二溶液中的所述阴离子包含放射性核素时，所述第一溶液中的所述阳离子相对于所述第二溶液中的所述阴离子的过量；所述第一溶液中的所述阳离子 可以完全沉淀掉所述第二溶液中的所述阴离子。
进一步地，当第二溶液中的所述阴离子包含放射性核素时，所述第二溶液中还可以包括非放射性阴离子，所述第一溶液中的所述阳离子还可以完全沉淀掉所述第二溶液中的所述非放射性阴离子。例如，所述第二溶液中的所述阴离子为 32PO 4 3-，所述第二溶液中还可以含有PO 4 3-，所述第一溶液中可以含有大量的Ca 2+，所述第一溶液中的Ca 2+可以完全沉淀掉第二溶液中的 32PO 4 3-和PO 4 3-。
例如，所述第二溶液中的所述非放射性阴离子可以是溶解在所述第二溶液中的第四可溶性盐中的阴离子，所述非放射性阴离子可以磷酸根、碳酸根、硫酸根、海藻酸根、氢氧根和硅酸根中的至少一种。
可选地，所述多孔固体载体的多孔孔洞内还含有水和可溶性金属盐，所述可溶性金属盐包括氯化钠、氯化钾、磷酸钠、磷酸钾、硫酸钠、硫酸钾、碳酸钠、碳酸钾、海藻酸钠、海藻酸钾、硅酸钠、和硅酸钾中的一种或多种。
本发明中，所述可溶性金属盐包括未反应完的所述第二可溶性盐，和由所述第二溶液与所述第一溶液反应生成的可溶性副盐。所述第二溶液与所述第一溶液反应生成的可溶性副盐是指，所述第一溶液中的阴离子和所述第二溶液中的阳离子形成的盐。可选地，所述第一溶液中的阴离子和所述第二溶液中的阳离子形成的盐可以但不限于包括氯化钠和氯化钾中的至少一种。
可选地，所述制备方法中，所述收集得到放射性颗粒的过程可以是直接收集得到所述放射性颗粒。所述收集得到放射性颗粒的过程还可以是间接收集得到所述放射性颗粒。例如，经去离子清洗、过滤和干燥等步骤后，收集所述放射性颗粒。
本发明中，经去离子水清洗、过滤和干燥等步骤后收集得到的所述放射性颗粒内的所述多孔孔洞内的水和可溶性金属盐可以被去除。
例如，经去离子水清洗、过滤和干燥等步骤后收集得到所述放射性颗粒，所述放射性颗粒的所述多孔孔洞内仅容置有放射性核素沉淀和所述第二沉淀。
本发明中，当所述放射性颗粒的多孔孔洞内的所述可溶性金属盐对人体无附加有害的副作用时，可以通过直接收集得到所述放射性颗粒。例如，所述可溶性金属盐可以但不限于为氯化钠、氯化钾或磷酸盐，或所述可溶性金属盐的量极少，不足以对人体造成伤害。
可选地，所述第一溶液的pH范围为6.0-8.0。进一步地，所述第一溶液的pH范围为6.5-7.5。
可选地，所述第二溶液的pH范围为6.0-12.0。进一步地，所述第二溶液的pH范围为6.5-10。
本发明所述制备方法中，所述第一溶液和所述第二溶液的总体积小于或等于所述多孔固体载体的总吸水量。
进一步地，所述第一溶液和所述第二溶液的总体积小于所述多孔固体载体的总吸水量。
本发明中，所述多孔固体载体为具有多孔孔洞的亲水性材料，且不溶于水。所述多孔固体载体也具有一定量的吸水量(water absorption)。即所述多孔固体载体可以吸附一定量的水溶液。不同材质的所述多孔固体载体的吸水量会存在差别。
所述多孔固体载体的总吸水量是指常温常压下，单位质量的多孔固体载体维持粉状(或单分散状态)下的最大吸收水的体积。所述多孔固体载体的吸水量的单位可以用体积单位表示，例如mL。
此外，所述多孔固体载体的总吸水量还可以通过所述多孔固体载体质量和所述多孔固体载体的吸水率换算得到。本发明所述多孔固体载体的吸水率是指多孔固体载体维持粉状吸收 的最大水溶液的质量与所述多孔固体载体干重的比率(％)。
本发明中，由于所述第一溶液和所述第二溶液的总体积小于或等于所述一定量的多孔固体载体的总吸水量，在所以放射性颗粒制备过程中，所述第一溶液和所述第二溶液会全部进入多孔固体载体的多孔孔洞内，并且制得的放射性颗粒为分散的粉状形态。
本发明中，所述第一溶液或所述第二溶液的体积均可以根据各自溶液中的溶质的浓度进行调节；以实现所述第二溶液的所述阴离子可以完全沉淀掉第一溶液中的所述含放射性核素的阳离子，或实现所述第一溶液的所述阳离子可以完全沉淀掉所述第二溶液中的含放射性核素的阴离子。
可选地，所述第一溶液与所述第二溶液的体积比为1：(0.1-10)。
进一步地，可选地，所述第一溶液与所述第二溶液的体积比为1：(0.5-2)。例如，本发明一实施方式中，所述第一溶液与所述第二溶液的体积比为1：1。
可选地，在缓慢滴加完所述第一溶液之后，缓慢滴加所述第二溶液之前，对所述多孔固体载体进行充分搅拌。其中，所述充分搅拌过程的搅拌转速可以为60-100转/分钟，搅拌时间为1-10分钟。通过对所述多孔固体载体进行搅拌，可以使所述第一溶液分散更均匀，且使所述第一溶液更加完全地进入所述多孔固体载体的多孔孔洞内。
进一步地，可选地，搅拌使所述第二溶液进入所述多孔孔洞内之后，对已经滴加完所述第一溶液和所述第二溶液的所述多孔固体载体进行充分搅拌。其中，所述充分搅拌过程的搅拌转速可以为60-100转/分钟，搅拌时间为1-10分钟。
通过对已经滴加完所述第一溶液和所述第二溶液的所述多孔固体载体进行充分搅拌，可以使所述第二溶液分散更均匀，使所述第二溶液更加完全地进入所述多孔固体载体的多孔孔洞内；更重要地是可以促使所述第二溶液中的所述阴离子与含所述金属放射性核素的所述阳离子更充分地形成放射性核素沉淀。
本发明所述制备方法中，所述多孔固体载体的粒径为0.05μm-600μm。
进一步地，可选地，所述多孔固体载体的粒径为0.05μm-600μm。
进一步地，可选地，所述多孔固体载体的粒径为10μm-500μm。
进一步地，可选地，所述多孔固体载体的粒径为10μm-300μm。
进一步地，可选地，所述多孔固体载体的粒径为10μm-100μm。
进一步地，可选地，所述多孔固体载体的粒径为30μm-80μm。
可选地，所述多孔固体载体的多孔孔径为0.1nm-600nm。
进一步地，可选地，所述多孔固体载体的多孔孔径为0.1nm-50nm。
进一步地，可选地，所述多孔固体载体的多孔孔径为0.1nm-20nm。
本发明中，所述多孔固体载体的多孔孔径为纳米级，非常小，所述放射性核素沉淀可以镶嵌在所述多孔固体载体的多孔孔洞内，结构稳定。经检测，本发明所述的放射性颗粒的放射性核素的释放率极低，放射性核素几乎不脱离多孔固体载体。
本发明中，所述多孔固体载体在用于制备所述放射性颗粒之前可以通过一粒径筛选过程。所述粒径筛选过程可以通过常规的筛选装置，例如通过一定孔径的筛选网等分级装置。
由于传统的放射性颗粒的制备方法繁琐复杂，耗时长，成本高，甚至存在环境污染。因此，相比于传统的制备方法，本发明开发的放射性颗粒的制备方法更加简单易操作；且整个制备过程耗时极短，尤其适用于制备半衰期很短的金属放射性核素的放射性颗粒。此外，本发明所述制备方法绿色环保，成本低。
第二方面，本发明提供了一种放射性颗粒，包括多孔固体载体和容置于所述多孔固体载体的多孔孔洞内的至少一种放射性核素沉淀；所述多孔固体载体具有亲水性，所述放射性核素沉淀由阳离子和阴离子反应生成，所述阳离子和/或所述阴离子包含放射性核素；所述多孔固体载体包括碳基材料、氧化铝颗粒、二氧化钛、硅藻土、凹凸棒土、沸石、金属有机框架材料和共价有机骨架聚合物中的至少一种。
本发明中，所述阳离子和/或所述阴离子包含放射性核素，包括以下三种实施方式：
本发明第一实施方式中，所述放射性核素沉淀由阳离子和阴离子反应生成，所述阳离子包含放射性核素，所述阴离子不含放射性核素。
本发明第二实施方式中，所述放射性核素沉淀由阳离子和阴离子反应生成，所述阴离子包含放射性核素，所述阳离子不含放射性核素。
本发明第三实施方式中，所述放射性核素沉淀由阳离子和阴离子反应生成，所述阳离子和所述阴离子均包含放射性核素。
可选地，所述阳离子包含金属放射性核素中的至少一种。
进一步地，可选地，所述阳离子包含的所述放射性核素可以但不限于包括锶、钇-90和镍-63中的至少一种。例如，所述阳离子为锶-90离子、钇-90离子和镍-63离子中的至少一种。
可选地，所述阴离子包含非金属放射性核素中的至少一种。
进一步地，可选地，所述阴离子包含的所述放射性核素可以但不限于包括磷-32，硫-35、碘-131和碘-125中的至少一种。例如，所述阴离子包括磷-32酸根、硫-35酸根、碘-131离子和碘-125离子中的至少一种。
可选地，当所述阴离子不包含所述放射性核素时，所述阴离子包括磷酸根、碳酸根、硫酸根、海藻酸根、氢氧根和硅酸根中的至少一种。
具体地，所述放射性核素沉淀可以但不限于选自磷酸钇-90、磷酸锶-90、碳酸镍-63、碘-125化银、碘-131化银和磷-32酸钙中的至少一种。所述放射性核素沉淀还可为磷-32酸钇-90或磷-32酸锶-90。
本发明中，所述放射性核素沉淀是指难溶于水的固体物质，在水溶液中几乎不游离出含放射性核素的阳离子或阴离子。且本发明所述放射性核素沉淀稳定地容置在多孔固体载体的多孔孔洞内，对温度和pH适用范围广，在人体温度和pH范围内十分稳定。
本发明中，容置于多孔孔洞内的放射性核素沉淀可以是一种，也可以是两种或两种以上放射性核素沉淀。每一种所述放射性核素沉淀可以是包含一种放射性核素，也可以是包含两种或两种以上放射性核素。
例如，本发明一实施方式中，所述放射性核素沉淀为含Sr-90的放射性核素沉淀、含Y-90的放射性核素沉淀或含Ni-63的放射性核素沉淀；本发明另一实施方式中，所述多孔孔洞内含两种放射性核素沉淀，其中一种放射性核素沉淀中包含Y-90；另一种放射性核素沉淀中包含Sr-90；在其他实施方式中，所述放射性核素沉淀可以同时含有两种放射性核素，例如放射性核素沉淀同时含有Sr-90和Y-90。
具体地，所述放射性核素沉淀可以但不限于选自磷酸钇-90、磷酸锶-90和碳酸镍-63中的至少一种。
本发明中，所述放射性颗粒的形状包括球形和非球形中的一种或多种。进一步地，所述放射性颗粒的形状包括球形、类球形、方形、棒状性、片状形和无规则形中的一种或多种。例如，本发明一实施方式中，所述放射性颗粒的形状为球形。
可选地，所述多孔固体载体的所述多孔孔洞内还包括第二沉淀，所述第二沉淀由非放射性金属阳离子和所述阴离子反应生成，所述非放射性金属阳离子包括锶离子、钇离子、镍离子、钙离子、银离子和镁离子中的一种或多种。
可选地，与所述非放射性金属阳离子反应生成是第二沉淀的所述阴离子可以包括放射性核素，也可以不包括放射性核素。本发明一实施方式中，当所述阴离子不包含所述放射性核素时，所述阴离子包括磷酸根、碳酸根、硫酸根、海藻酸根、氢氧根和硅酸根中的至少一种。当所述阴离子包含放射性核素时，所述阴离子包含的所述放射性核素可以但不限于包括磷-32，硫-35和碘-125、碘-131中的至少一种。
进一步地，可选地，所述非放射性金属阳离子与反应生成所述放射性沉淀的所述阳离子可以互为同位素。例如，本发明一实施方式中，反应生成所述放射性核素沉淀的所述阳离子为钇-90离子时，所述非放射性金属阳离子为钇89离子。本发明另一实施方式，反应生成所述放射性核素沉淀的所述阳离子为镍-63离子时，所述非放射性金属阳离子为镍58离子。
可选地，当反应生成所述放射性核素沉淀的所述阳离子没有对应的稳定同位素时，所述非放射性金属阳离子可以选自钙离子、镁离子和银离子中的至少一种。
可选地，所述多孔固体载体的所述多孔孔洞内还包括水和可溶性金属盐，所述可溶性金属盐包括氯化钠、氯化钾、磷酸钠、磷酸钾、硫酸钠、硫酸钾、碳酸钠、碳酸钾、海藻酸钠、海藻酸钾、硅酸钠和硅酸钾中的一种或多种。
可选地，所述多孔固体载体的多孔孔径为0.1nm-600nm。
进一步地，可选地，所述多孔固体载体的多孔孔径为0.1nm-50nm。
进一步地，可选地，所述多孔固体载体的多孔孔径为0.1nm-20nm。
本发明中，所述多孔固体载体的多孔孔径为纳米级，非常小，所述放射性核素沉淀可以镶嵌在所述多孔固体载体的多孔孔洞内，结构稳定。经检测，本发明所述的放射性颗粒的放射性核素的释放率极低，放射性核素几乎不脱离多孔固体载体。
可选地，所述多孔固体载体的粒径为0.05μm-600μm。
进一步地，可选地，所述多孔固体载体的粒径为10μm-500μm。
进一步地，可选地，所述多孔固体载体的粒径为10μm-300μm。
进一步地，可选地，所述多孔固体载体的粒径为10μm-100μm。
进一步地，可选地，所述多孔固体载体的粒径为30μm-80μm。
进一步地，可选地，所述多孔固体载体的粒径为30μm-60μm。例如，所述多孔固体载体颗粒的粒径可以但不限于为30μm，或为35μm，或为40μm，或为45μm，或为50μm，或为55μm，或为60μm。
本发明所述放射性颗粒中，单位质量的多孔固体载体的多孔孔洞内的放射性核素沉淀的质量可以根据实际需求进行调整。相应地，所述放射性颗粒中所述放射性核素的放射性活度也可以根据实际需求进行调节。
可选地，每克所述放射性颗粒中的所述放射性核素的放射性活度为0.1GBq-50GBq。进一步地，可选地，每克所述放射性颗粒中的所述放射性核素的放射性活度为0.1GBq-30GBq。
本发明第二方面的所述放射性颗粒，由本发明第一方面所述的制备方法制备得到。
第三方面，本发明还提供了一种如本发明第一方面所述的制备方法制备的放射性颗粒在制备用于治疗肿瘤的药物中的应用。
由于本发明所述放射性颗粒具有结构稳定，放射性核素的释放率低，安全性高和成本低 的特点，因此，本发明所述放射性颗粒在制备用于治疗肿瘤的药物领域具有广阔的应用前景。
例如，本发明还提供了一种用于放射性治疗的制剂，包括所述放射性颗粒和药学上可接受的赋形剂。
本发明所述药学上可接受的赋形剂是指不会带来副作用的辅剂。可选地，所述赋形剂可以但不限于包括稀释剂、粘合剂、填充剂、涂膜聚合物、增塑剂、助流剂、崩解剂、润滑剂和释放速度调节剂。
本发明一实施方式中，所述赋形剂可以是生理盐水。由于本发明所述放射性颗粒具有亲水性；因此，所述放射性颗粒可以均匀分布在所述生理盐水中。
本发明所述放射性颗粒可以含有至少一种放射性核素，所述放射性颗粒的放射性活度可以调节控制放射性核素沉淀含量来进行控制；并且，所述放射性颗粒结构稳定，放射性核素的释放率低，粒径范围为0.05-600μm；可以用于制得绝大部分医用的放射性治疗的制剂；所述制剂可以广泛用于治疗各种肿瘤等疾病的放疗药物。
本发明一实施方式中，所述制剂可以通过灌注的方式到达肿瘤部位，所述制剂中包含的放射性颗粒的多孔孔洞内放射性核素沉淀，可以发射β射线对肿瘤进行杀伤而达到治疗的目的；所述用于放射性治疗的制剂还可以有效控制肿瘤侵袭和转移，其对于肿瘤细胞具有很强的杀伤作用，而对肿瘤周边的正常细胞伤害却十分低。
本发明所述制剂除了可以应用于肝癌的动脉灌注栓塞放疗外，还可以用于其他恶性肿瘤的放疗，例如，乳腺癌、肺癌、肾癌或舌癌等。
本发明的有益效果包括：
(1)本发明所述放射性颗粒的制备方法，简单易操作，整个制备过程耗时极短，可以用于制备含半衰期很短的放射性核素的放射性颗粒；本发明所述制备方法中的放射性核素利用率极高，绿色环保，成本低，可以适用于工业化的大规模生产。
(2)本发明所述放射性颗粒包括多孔固体载体和容置于多孔固体载体的多孔孔洞内的至少一种放射性核素沉淀；所述放射性颗粒结构稳定，放射性核素的释放率低，并且所述放射性颗粒的粒径尺寸、放射性核素沉淀中放射性核素的种类和放射性活度均可调节，安全性高，具有广阔的应用前景。
(3)本发明所述放射性颗粒在制备用于治疗肿瘤的药物领域具有广阔的应用前景，其具有安全性高、成本低等特点，所述放射性颗粒的放射性活度和放射性颗粒粒径尺寸可以根据实际需求进行调控，可用于多种恶性肿瘤的放疗制剂。
附图说明
图1是本发明一实施例中放射性颗粒制备方法的流程示意图。
具体实施方式
以下所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也视为本发明的保护范围。
若无特别说明，所述制备方法中使用的化学试剂均为市售试剂。
请参考图1，图1是本发明一实施例提供的放射性颗粒的制备方法的流程示意图，包括以下步骤：
S10、配制第一溶液，所述第一溶液中含有至少一种阳离子；
S20、配制第二溶液，所述第二溶液中含有至少一种阴离子，所述阳离子和/或所述阴离子包含放射性核素，所述阴离子能与所述阳离子反应生成放射性核素沉淀；
S30、取一定量亲水性的多孔固体载体，先将所述第一溶液缓慢滴加至所述多孔固体载体中，并充分搅拌使所述第一溶液进入所述多孔固体载体的多孔孔洞内；再将所述第二溶液缓慢滴加至所述多孔固体载体中，搅拌使所述第二溶液进入所述多孔孔洞内，所述第二溶液中的阴离子与所述第一溶液中的金属阳离子在所述多孔孔洞内反应生成所述放射性核素沉淀，所述放射性核素沉淀容置于所述多孔孔洞内，然后收集得到放射性颗粒；其中，所述多孔固体载体包括碳基材料、氧化铝颗粒、二氧化钛、硅藻土、凹凸棒土、沸石、金属有机框架材料和共价有机骨架聚合物中的至少一种。
可选地，所述放射性颗粒的制备方法中，还可以在进行制备之前，先配制好所述第一溶液和/或所述第二溶液。当所述放射性核素的半衰期很短时，可以选择在制备过程中临时配置。
下面分多个实施例对本发明实施例进行进一步的说明。
对照组1(冷实验)
本实施方式中的对照组1是严格按照本发明所述放射性颗粒的制备方法的步骤实行，其区别在于：将放射性核素Y-90溶液换成其无放射性的稳定同位素Y-89溶液，目的是为了方便离子浓度检测，并且减少放射性核素对检测人员和设备的损伤。
一种含磷酸钇(Y-89)的非放射性颗粒的制备方法，包括：
称取氯化钙和六水氯化钇，去离子水溶解，充分混匀后，配制1L含1mol/L的氯化钙和10 -6mol/L(约89ppm)的氯化钇的第一溶液；
称取磷酸钠，用去离子水溶解，充分混匀后，配制1L含0.7mol/L的磷酸钠的第二溶液；
称取20g单分散的多孔固体载体并置于广口容器中，该多孔固体载体的粒径约为50μm，其中，该多孔固体载体的总吸水量约为20mL，向容器中缓慢滴加10mL第一溶液，边滴加边搅拌多孔固体载体；滴加完后再搅拌10分钟充分分散多孔固体载体。然后向容器中缓慢滴加10mL第二溶液，边滴加边搅拌，滴加完后再搅拌10分钟；然后收集得到含磷酸钇的非放射性颗粒。
实施例1
一种含钇-90的放射性颗粒的制备方法，包括：
称取医用放射性氯化钇-90溶液10mL，使用放射性活度计测量其放射性活度为10GBq；向溶液中加入约1.11g无水氯化钙，充分混匀后，配制得到含0.01mol氯化钙和10GBq氯化钇-90的第一溶液。
称取磷酸钠，用去离子水溶解，配制1L含0.7mol/L的磷酸钠的第二溶液；
称取20g单分散的多孔活性炭颗粒并置于广口容器中，该多孔活性炭颗粒的粒径约为50μm，其中，该多孔活性炭颗粒的总吸水量约为20mL，向容器中缓慢滴加全部第一溶液，边滴加边搅拌多孔活性炭颗粒；滴加完后再搅拌10分钟充分分散多孔活性炭颗粒。然后向容器中缓慢滴加10mL第二溶液，边滴加边搅拌，滴加完后再搅拌10分钟；然后收集得到含钇-90的放射性颗粒。
本实施例1的制备过程中，第二溶液为提前配制，配制第一溶液开始计时，最后收到含钇-90的放射性颗粒的耗时约35分钟。称取1g制备得到的含钇-90的放射性颗粒，用放射性活度计进行测试，测得1g放射性颗粒的放射性活度为0.25GBq。并且通过对制得的放射性颗 粒和使用的多孔活性炭颗粒进行表征，可以发现放射性颗粒和多孔活性炭颗粒的表面形貌无明显差别。
实施例2
一种含钇-90的放射性颗粒的制备方法，包括：
称取医用放射性氯化钇-90溶液20mL，使用放射性活度计测量其放射性活度为40GBq；向溶液中加入约2.78g无水氯化钙，充分混匀后，配制得到含0.025mol氯化钙和50GBq氯化钇-90的第一溶液。
称取磷酸钠，用去离子水溶解，配制1L含0.7mol/L的磷酸钠的第二溶液；
称取50g单分散的多孔硅藻土颗粒并置于广口容器中，该多孔硅藻土颗粒的粒径约为60μm，其中，该多孔硅藻土颗粒的总吸水量约为40mL，向容器中缓慢滴加全部第一溶液，边滴加边搅拌多孔硅藻土颗粒；滴加完后再搅拌10分钟充分分散多孔硅藻土颗粒。然后向容器中缓慢滴加20mL第二溶液，边滴加边搅拌，滴加完后再搅拌10分钟；然后收集得到含钇-90的放射性颗粒。
本实施例2的制备过程中，第二溶液为提前配制，配制第一溶液开始计时，最后收到含钇-90的放射性颗粒的耗时约40分钟。称取1g制备得到的含钇-90的放射性颗粒，用放射性活度计进行测试，测得1g放射性颗粒的放射性活度为0.44GBq。
实施例3
一种含钇-90的放射性颗粒的制备方法，包括：
称取医用放射性氯化钇-90溶液25mL，使用放射性活度计测量其放射性活度为50GBq；向溶液中加入约7.6g六水氯化钇固体，充分混匀后，配制得到含0.025mol氯化钇和50GBq氯化钇-90的第一溶液。
称取磷酸钠，用去离子水溶解，配制1L含1.1mol/L的磷酸钠的第二溶液；
称取50g单分散的多孔活性炭颗粒并置于广口容器中，该多孔活性炭颗粒的粒径约为30μm，其中，该多孔活性炭颗粒的总吸水量约为50mL，向容器中缓慢滴加约全部第一溶液，边滴加边搅拌多孔活性炭颗粒；滴加完后再搅拌10分钟充分分散多孔活性炭颗粒。然后向容器中缓慢滴加25mL第二溶液，边滴加边搅拌，滴加完后再搅拌10分钟；然后收集得到含钇-90的放射性颗粒。
本实施例3的制备过程中，第二溶液为提前配制，配制第一溶液开始计时，最后收到含钇-90的放射性颗粒的耗时约44分钟。称取1g制备得到的含钇-90的放射性颗粒，用放射性活度计进行测试，测得1g放射性颗粒的放射性活度为0.50GBq。
实施例4
一种含钇-90的放射性颗粒的制备方法，包括：
称取医用放射性氯化钇-90溶液25mL，使用放射性活度计测量其放射性活度为50GBq；向溶液中加入约2.38g氯化镁，充分混匀后，配制得到含0.025mol氯化镁和50GBq氯化钇-90的第一溶液。
称取磷酸钠，用去离子水溶解，配制1L含1.0mol/L的磷酸钠的第二溶液；
称取50g单分散的多孔活性炭颗粒并置于广口容器中，该多孔活性炭颗粒的粒径约为 30μm，其中，该多孔活性炭颗粒的总吸水量约为50mL，向容器中缓慢滴加全部第一溶液，边滴加边搅拌多孔活性炭颗粒；滴加完后将多孔活性炭颗粒转移到分散机中，在100转/分钟的条件下分散5分钟。然后向容器中缓慢滴加25mL第二溶液，边滴加边搅拌，滴加完后将多孔活性炭颗粒转移到分散机中，在100转/分钟的条件下分散5分钟；然后收集得到含钇-90的放射性颗粒。
本实施例4的制备过程中，第二溶液为提前配制，配制第一溶液开始计时，最后收到含钇-90的放射性颗粒的耗时约40分钟。称取1g制备得到的含钇-90的放射性颗粒，用放射性活度计进行测试，测得1g放射性颗粒的放射性活度为0.50GBq。
实施例5
一种含锶-90的放射性颗粒的制备方法，包括：
称取医用放射性氯化锶-90溶液10mL，使用放射性活度计测量其放射性活度为16GBq；向溶液中加入约1.11g无水氯化钙，充分混匀后，配制得到含0.01mol氯化钙和16GBq氯化锶-90的第一溶液。
称取磷酸钠，用去离子水溶解，配制1L含0.7mol/L的磷酸钠的第二溶液；
称取20g单分散的多孔活性炭颗粒并置于广口容器中，该多孔活性炭颗粒的粒径约为50μm，其中，该多孔活性炭颗粒的总吸水量约为20mL，向容器中缓慢滴加全部第一溶液，边滴加边搅拌多孔活性炭颗粒；滴加完后再搅拌10分钟充分分散多孔活性炭颗粒。然后向容器中缓慢滴加10mL第二溶液，边滴加边搅拌，滴加完后再搅拌10分钟；然后收集得到含锶-90的放射性颗粒。
本实施例5的制备过程中，第二溶液为提前配制，配制第一溶液开始计时，最后收到含锶-90的放射性颗粒的耗时约35分钟。称取1g制备得到的含锶-90的放射性颗粒，用放射性活度计进行测试，测得1g放射性颗粒的放射性活度为0.40GBq。
实施例6
一种含镍-63的放射性颗粒的制备方法，包括：
称取医用放射性镍-63离子溶液10mL，使用放射性活度计测量其放射性活度为16GBq；向溶液中加入约1.11g无水氯化钙，充分混匀后，配制得到含0.01mol氯化钙和16GBq镍-63离子的第一溶液。
称取磷酸钠，用去离子水溶解，配制1L含1.1mol/L的碳酸钠的第二溶液；
称取20g单分散的多孔硅藻土颗粒并置于广口容器中，该多孔硅藻土颗粒的粒径约为50μm，其中，该多孔硅藻土颗粒的总吸水量约为20mL，向容器中缓慢滴加全部第一溶液，边滴加边搅拌多孔硅藻土颗粒；滴加完后再搅拌10分钟充分分散多孔硅藻土颗粒。然后向容器中缓慢滴加10mL第二溶液，边滴加边搅拌，滴加完后再搅拌10分钟；然后收集得到含镍-63的放射性颗粒。
本实施例5的制备过程中，第二溶液为提前配制，配制第一溶液开始计时，最后收到含镍-63的放射性颗粒的耗时约35分钟。称取1g制备得到的含镍-63的放射性颗粒，用放射性活度计进行测试，测得1g放射性颗粒的放射性活度为0.40GBq。
实施例7
一种含磷-32的放射性颗粒的制备方法，包括：
称取无水氯化钙，加入去离子水，充分混匀后，定容至10mL，配制得到含0.015mol氯化钙的第一溶液。
称取医用放射性磷-32酸钠溶液10mL，使用放射性活度计测量其放射性活度为10GBq；向溶液中加入约普通磷酸钠固体，充分混匀后，配制得到含约0.007mol磷酸钠和10GBq磷-32酸钠的第二溶液。
称取20g单分散的多孔活性炭颗粒并置于广口容器中，该多孔活性炭颗粒的粒径约为50μm，其中，该多孔活性炭颗粒的总吸水量约为20mL，向容器中缓慢滴加全部第一溶液，边滴加边搅拌多孔活性炭颗粒；滴加完后再搅拌10分钟充分分散多孔活性炭颗粒。然后向容器中缓慢滴加全部第二溶液，边滴加边搅拌，滴加完后再搅拌10分钟；然后收集得到含磷-32的放射性颗粒。
本实施例7的制备过程中，第二溶液为提前配制，配制第一溶液开始计时，最后收到含磷-32的放射性颗粒的耗时约35分钟。称取1g制备得到的含磷-32的放射性颗粒，用放射性活度计进行测试，测得1g放射性颗粒的放射性活度为0.25GBq。
实施例8
一种含碘-125的放射性颗粒的制备方法，包括：
称取硝酸银，加入去离子水，充分混匀后，定容至10mL，配制得到含0.012mol硝酸银的第一溶液。
称取医用放射性碘-125化钠溶液10mL，使用放射性活度计测量其放射性活度为10GBq；向溶液中加入氯化钠固体，充分混匀后，配制得到含约0.01mol氯化钠和10GBq碘-125化钠的第二溶液。
称取20g单分散的多孔活性炭颗粒并置于广口容器中，该多孔活性炭颗粒的粒径约为50μm，其中，该多孔活性炭颗粒的总吸水量约为20mL，向容器中缓慢滴加全部第一溶液，边滴加边搅拌多孔活性炭颗粒；滴加完后再搅拌10分钟充分分散多孔活性炭颗粒。然后向容器中缓慢滴加全部第二溶液，边滴加边搅拌，滴加完后再搅拌10分钟；然后收集得到含碘-125的放射性颗粒。
本实施例8的制备过程中，第二溶液为提前配制，配制第一溶液开始计时，最后收到含碘-125的放射性颗粒的耗时约35分钟。称取1g制备得到的含碘-125的放射性颗粒，用放射性活度计进行测试，测得1g放射性颗粒的放射性活度为0.25GBq。
效果实施例一
放射性活性检测
分别称取实施例1-8中制备的放射性颗粒各1g，分别命名为实验组1-实验组8。向各组的放射性颗粒中，加入10％生理盐水20mL，密封。然后置于50摄氏度恒温箱中，放置24小时后，离心收集取滤液，用放射性活度计分别对滤液进行测试，结果参见表1。
表1实验组放射性活度的检测数据表
实验组 放射性活度(GBq)
实验组1 0
实验组2 0
实验组3 0
实验组4 0
实验组5 0
实验组6 0
实验组7 0
实验组8 0
由测试数据可知，本发明实施例1-8制备的放射性颗粒都表现出良好的结构稳定性，在长时间的浸泡下，均为检测出放射性活度，其放射性核素的释放率接近为0％，说明由本发明所述制备方法值得的放射性颗粒中的放射性核素不会出现泄漏风险。
效果实施例二
离子浓度检测
取对照组1所述制备方法制得3g含钇89的非放射性颗粒，加入10％生理盐水20mL，密封。然后置于50℃恒温箱中，每天取出振荡5min，放置14天。14天后，离心收集取滤液，用ICP(电感耦合等离子光谱仪)测试滤液中钇离子浓度。
其中，ICP测试结果显示滤液中钇离子浓度＜0.02mg/L(低于检出限，即未检出钇离子)。
然后，称取0.3g的非放射性颗粒，加入20mL 10％硝酸溶液，浸泡4小时，定容至50mL，离心收集取滤液，用ICP进行测试滤液中钇离子浓度。
其中，ICP测试结果显示滤液中钇离子浓度为40ppm。
由上述测试数据分析得到，对比组1所述制备方法制得的含钇89的非放射性颗粒中，钇是以沉淀形式容置在所述多孔固体载体的多孔孔洞内，且结构稳定，在长达14天的浸泡中，钇离子的几乎无释放。通过用硝酸溶解所述多孔孔洞内的磷酸钇沉淀之后，才可以检测到钇离子从非放射性颗粒内释放出来。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也视为本发明的保护范围。

Claims (20)

  1. 一种放射性颗粒的制备方法，其中，包括：
    配制第一溶液，所述第一溶液中含有至少一种阳离子；
    配制第二溶液，所述第二溶液中含有至少一种阴离子，所述阳离子和/或所述阴离子包含放射性核素，所述阴离子能与所述阳离子反应生成放射性核素沉淀；
    取一定量亲水性的多孔固体载体，先将所述第一溶液缓慢滴加至所述多孔固体载体中，并充分搅拌使所述第一溶液进入所述多孔固体载体的多孔孔洞内；再将所述第二溶液缓慢滴加至所述多孔固体载体中，搅拌使所述第二溶液进入所述多孔孔洞内，所述第二溶液中的阴离子与所述第一溶液中的金属阳离子在所述多孔孔洞内反应生成所述放射性核素沉淀，所述放射性核素沉淀容置于所述多孔孔洞内，然后收集得到放射性颗粒；其中，所述多孔固体载体包括碳基材料、氧化铝颗粒、二氧化钛、硅藻土、凹凸棒土、沸石、金属有机框架材料和共价有机骨架聚合物中的至少一种。
  2. 如权利要求1所述的制备方法，其中，所述第一溶液中的所述阳离子包括锶-90离子、钇-90离子和镍-63离子中的至少一种；所述第二溶液中的所述阴离子中包含的放射性核素包括磷-32、硫-35、碘-131和碘-125中的至少一种。
  3. 如权利要求1所述的制备方法，其中，当所述阴离子不包含所述放射性核素时，所述阴离子包括磷酸根、碳酸根、硫酸根、氢氧根、海藻酸根和硅酸根中的至少一种。
  4. 如权利要求1所述的制备方法，其中，当所述阳离子不包含所述放射性核素时，所述阳离子包括银离子、钙离子和镁离子中的至少一种。
  5. 如权利要求1-4任意一项所述的制备方法，其中，所述第一溶液中还包括非放射性金属阳离子，所述非放射性金属阳离子能与所述第二溶液中的所述阴离子反应生成第二沉淀；所述非放射性金属阳离子包括锶离子、钇离子、镍离子、钙离子、银离子和镁离子中的一种或多种。
  6. 如权利要求1所述的制备方法，其中，所述第一溶液和所述第二溶液的总体积小于或等于所述多孔固体载体的总吸水量。
  7. 如权利要求1-4任意一项所述的制备方法，其中，所述多孔固体载体的粒径为0.05μm-600μm。
  8. 如权利要求1-4任意一项所述的制备方法，其中，所述多孔固体载体的多孔孔径为0.1nm-600nm。
  9. 如权利要求1-4任意一项所述的制备方法，其中，每一克重量的所述放射性颗粒中，所述放射性核素的放射性活度为0.1GBq-50GBq。
  10. 一种放射性颗粒，其中，包括多孔固体载体和容置于所述多孔固体载体的多孔孔洞内的至少一种放射性核素沉淀；所述多孔固体载体具有亲水性，所述放射性核素沉淀由阳离子和阴离子反应生成，所述阳离子和/或所述阴离子包含放射性核素；所述多孔固体载体包括碳基材料、氧化铝颗粒、二氧化钛、硅藻土、凹凸棒土、沸石、金属有机框架材料和共价有机骨架聚合物中的至少一种。
  11. 如权利要求10所述的放射性颗粒，其中，所述阳离子包含的所述放射性核素包括锶-90、钇-90和镍-63中的至少一种。
  12. 如权利要求10所述的放射性颗粒，其中，所述阴离子包含的所述放射性核素包括磷-32、硫-35、碘-131和碘-125中的至少一种。
  13. 如权利要求10所述的放射性颗粒，其中，当所述阴离子不包含所述放射性核素时，所述阴离子包括磷酸根、碳酸根、硫酸根、氢氧根、海藻酸根和硅酸根中的至少一种。
  14. 如权利要求10所述的放射性颗粒，其中，当所述阳离子不包含所述放射性核素时，所述阳离子包括银离子、钙离子和镁离子中的至少一种。
  15. 如权利要求10所述的放射性颗粒，其中，所述放射性核素沉淀包括磷酸钇-90、磷酸锶-90、碳酸镍-63、碘-125化银、碘-131化银和磷-32酸钙中的至少一种。
  16. 如权利要求10-15任意一项所述的放射性颗粒，其中，所述多孔固体载体的所述多孔孔洞内还包括第二沉淀，所述第二沉淀由非放射性金属阳离子和所述阴离子反应生成，所述非放射性金属阳离子包括锶离子、钇离子、镍离子、钙离子和镁离子中的一种或多种。
  17. 如权利要求10-15任意一项所述的放射性颗粒，其中，每一克重量的所述放射性颗粒中，所述放射性核素的放射性活度为0.1GBq-50GBq。
  18. 如权利要求10-15任意一项所述的放射性颗粒，其中，所述多孔固体载体的所述多孔孔洞内还包括水和可溶性金属盐，所述可溶性金属盐包括氯化钠、氯化钾、磷酸钠、磷酸钾、硫酸钠、硫酸钾、碳酸钠、碳酸钾、海藻酸钠、海藻酸钾、硅酸钠和硅酸钾中的一种或多种。
  19. 如权利要求10-15任意一项所述的放射性颗粒，其中，所述多孔固体载体的粒径为0.05μm-600μm；所述多孔固体载体的多孔孔径为0.1nm-600nm。
  20. 一种如权利要求1-9任意一项所述的制备方法制备的放射性颗粒或如权利要求10-19任意一项所述放射性颗粒在制备用于治疗肿瘤的药物中的应用。
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