CN114652862A - Radioactive resin microsphere injection, preparation method and application - Google Patents
Radioactive resin microsphere injection, preparation method and application Download PDFInfo
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- CN114652862A CN114652862A CN202011534114.6A CN202011534114A CN114652862A CN 114652862 A CN114652862 A CN 114652862A CN 202011534114 A CN202011534114 A CN 202011534114A CN 114652862 A CN114652862 A CN 114652862A
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- microspheres
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- radioactive resin
- injection
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- 238000002347 injection Methods 0.000 title claims abstract description 93
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- 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
- 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
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
-
- 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
- A61K51/1213—Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature
Abstract
The invention belongs to the technical field of medicines, and discloses a radioactive resin microsphere injection, a preparation method and application thereof, wherein each 1ml of the radioactive resin microsphere injection comprises: 0.1-300mg of radioactive resin microspheres and 1-0.75ml of hydrogel. The injection is used for preparing a medicament for treating tumors, can be directly injected into the tumors in an intervention mode, can directly determine the radioactive dose of the radioactive resin microspheres through the administration volume, reaches the hydrogel in the tumors and can form gel with calcium ions in the tumors, so that the radioactive resin microspheres are uniformly dispersed and limited in the tumors, high-dose local radiotherapy is provided through the radioactive resin microspheres to realize the treatment of solid tumors, and the injection has wide application prospect in the treatment of the solid tumors.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a radioactive resin microsphere injection, a preparation method and application thereof.
Background
The prior radioactive resin microsphere product clinically applied mainly comprises yttrium [ 2 ]90Y]Resin microspheres SIR-Spheres (Sirtex Medical Limited) and holmium [ holmium ] being subjected to clinical trial research166Ho]The two types of resin microsphere products are radioactive resin microsphere products dispersed in water for sterilization injection or 0.9 percent sodium chloride injection solution, and the products can not be administrated in a mode of direct injection by an injector due to the fact that the products are quickly settled and easily subjected to needle blockage. For the purpose of convenient administration and radiation shielding, the administration is carried out by means of an infusion administration device as shown in fig. 1, and the administration method needs to be flushed by using 20-60ml of injection liquid to carry radioactive microspheres into a body along a catheterAnd (4) the following steps. Although this approach can achieve better drug delivery, there are significant limitations, 1, the large volume of drug delivery cannot be used for intratumoral drug delivery but only for intravascular drug delivery; 2. the purpose of quantitative administration of radioactive dose of radioactive microspheres cannot be achieved depending on the administration volume. These limitations make SIR-Spheres and QuriemSphere @ only be used for the treatment of solid tumors with abundant arterial blood supply through the mode of arterial cannula interventional drug delivery, but not be used for the treatment of other solid tumors through the mode of intratumoral direct injection, so that the expansion of the indications is limited. Therefore, development of novel formulations is required.
The density of the resin microspheres is generally 1.1-1.6g/cm3In order to achieve the purpose that the resin microspheres can be directly injected for administration, a non-radioactive resin microsphere product is taken as an example: the microsphere products of small molecules and polypeptides developed at home and abroad, such as: the risperidone sustained-release microspheres, the exenatide sustained-release microspheres and the like usually take sodium carboxymethyl cellulose, span 80, tween 80, stearic acid, sodium dodecyl benzene sulfonate, fatty glyceride and the like as suspending agents, and the suspension of the resin microspheres in a solution is realized mainly by adjusting the hydrophily and hydrophobicity and viscosity of the solution. However, the preparation is a non-radioactive microsphere product, and can be directly injected for administration after being shaken and uniformly mixed in the using process, so that the possibility of needle blockage is low, and the consequences are not serious even if the needle blockage occurs. The radioactive microsphere product is inconvenient to shake up before administration and the radioactive leakage can cause serious consequences if a needle is blocked, so that higher requirements are made on the administration process and the design of the product. Furthermore, the decay of radioactive doses over time, which corresponds to a reduction in the amount of drug, often requires recalculation of the radioactive dose at the site of administration and taking and activity measurements of the drug in the calculated amount at the site to obtain an accurate radiopharmaceutical dose. This process is cumbersome and presents a significant radiation safety risk. If the radiopharmaceutical used is homogeneous, for example: the solution can be directly used for determining the dosage to be administrated through the volume without measuring and taking the activity on site. While the radioactive microsphere products reported at present,such as: the above-mentioned yttrium [ 2 ]90Y]Resin microsphere SIR-Spheres and holmium duration166Ho]The resin microspheres (QuriemSephere) are all heterogeneous, and cannot be used for accurately determining the radioactive administration dose according to the administration volume.
Disclosure of Invention
In order to solve the technical problems in the background art, the invention provides a radioactive resin microsphere injection, a preparation method and application thereof, wherein the radioactive resin microsphere injection is low in viscosity and good in fluidity, and the radioactive resin microspheres are uniformly dispersed in a medium, do not settle for a long time and can be directly injected for use.
In a first aspect, the invention also provides a radioactive resin microsphere injection.
In the research of the applicant, a sodium alginate solution with a certain concentration has a certain suspending effect on the dispersion of the resin microspheres in water, but the resin microspheres dispersed in the sodium alginate solution are completely settled within 10 minutes. Further, sodium alginate and divalent metal ions are combined to form gel, so that the resin microspheres can be uniformly dispersed, and the resin microspheres can be uniformly dispersed in the gel with the optimized prescription for a long time without sedimentation.
Specifically, the radioactive resin microsphere injection comprises the following components in 1 ml: 0.1-300mg of radioactive resin microspheres and 1-0.75ml of hydrogel resin microspheres.
Further research shows that by optimizing the proportion and the dosage of the sodium alginate and the divalent metal ions, the resin microsphere injection can keep good fluidity when the resin microspheres are ensured not to be settled, and the administration can be realized by a direct injection mode. By adding a small amount of divalent metal ions, the viscosity of the sodium alginate solution is remarkably reduced, such as: the viscosity of 0.2% sodium alginate solution is about 30 mPa.S, the viscosity of hydrogel formed by the solution is different according to the adding amount of divalent metal ions, and when the mass ratio of sodium alginate to calcium ions is 1: the hydrogel viscosity is 5-20 mPa.S when the viscosity is 0.05-0.15. The viscosity is reduced, so that the resistance in the injection process is smaller, the needle adaptability is better, the injection is easier, air bubbles in the injection are easier to discharge, and more importantly, the viscosity is reduced, the dispersion of the radioactive resin microspheres in the hydrogel is more uniform, and the radioactive resin microspheres do not settle for a long time.
Specifically, the mass ratio of the sodium alginate to the divalent metal ions is 1: (0.02-0.3), preferably 1: (0.05-0.15).
Further, the hydrogel has a viscosity of between 1 and 100 mPa.S, preferably between 5 and 20 mPa.S.
Further, the divalent metal ions refer to divalent metal ions with good biocompatibility, and can be mixed with a sodium alginate solution and then instantaneously react to combine into hydrogel, such as calcium ions and strontium ions, and preferably calcium ions.
Further, the radionuclide loaded on the radioactive resin microspheres may be any nuclide for therapeutic and/or imaging that can be stably loaded on the resin microspheres, including but not limited to: yttrium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha90Y]Technetium [ alpha ]99mTc]Lutetium [ lutetium ]177Lu]Holmium [ 2 ]166Ho]Samarium [ 2 ]153Sm]Rhenium [ alpha ], [186Re]Rhenium [ alpha ], [ alpha, and [ alpha ], [ alpha188Re]Zirconium [ 2 ]89Zr]Gallium 268Ga]Iodine [ iodine ]131I]Iodine [ iodine ]125I]2, phosphorus32P]Copper [ 2 ]64Cu]Chinese medicine' Jing223Ra]Thorium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha ]227Th]Actinium [ 2 ], [225Ac]Lead 2212Pb]Any one or more of.
Further research shows that the radioactive resin microsphere injection is macroscopically homogeneous-like, that is, the quantity of the radioactive resin microspheres contained in the injection and the radioactive dose are basically equal by taking equal volume of the injection. Therefore, the volume of the injection can be controlled to realize accurate quantitative administration of the radioactive resin microspheres.
Further studies have found that the dose of radioactivity contained per unit volume is adjustable in the range of 0-5GBq/ml, but that the hydrogel is subject to radiation degradation in a short time when the radioactive dose of the radioactive resin microspheres exceeds 5GBq/ml, so that the viscosity of the composition is significantly reduced and the homogeneity is destroyed.
Specifically, the radioactivity of the radioactive resin microspheres is 0-5GBq per milliliter of radioactive resin microspheres in the injection, so that the radioactive concentration of the radioactive resin microsphere injection can be adjusted within a certain range.
Further research shows that the radioactive resin microsphere with the particle size smaller than 1 micron can be uniformly and stably dispersed in the aqueous solution of high-molecular suspending agent such as sodium carboxymethyl cellulose, and the particles with the particle size of 1-1000 microns cannot be uniformly and stably dispersed in the ordinary high-molecular suspending agent solution for a long time, and can be uniformly and stably dispersed in calcium alginate hydrogel for a long time. However, when the particle size of the resin microspheres is larger than 300 μm, smooth administration by direct injection is difficult, and particles having a particle size of less than 20 μm easily migrate to other tissues and organs in vivo.
Specifically, the particle size of the radioactive resin microspheres is 1-1000 μm, preferably 20-300 μm, so that the radioactive resin microspheres are uniformly dispersed in the hydrogel system.
Further research shows that the radioactive resin microspheres prepared by using polystyrene microspheres, polyethylene microspheres, polydivinylbenzene microspheres, polylactic acid microspheres, polyglycolide-lactide microspheres, polylactide microspheres, chitosan microspheres, calcium alginate microspheres, dextran microspheres and albumin microspheres as carriers can be stably and uniformly dispersed in hydrogel.
Further, the radioactive resin microspheres include radioactive resin microspheres prepared by any method, including but not limited to: any one or more of polystyrene microspheres, polyethylene microspheres, polydivinylbenzene microspheres, polylactic acid microspheres, polyglycolide-lactide microspheres, polylactide microspheres, chitosan microspheres, calcium alginate microspheres, dextran microspheres and poly-albumin microspheres.
In a second aspect, the present invention also provides a method for preparing a radioactive resin microsphere injection, which comprises the following two preparation methods:
in one embodiment, the radioactive resin microspheres are directly and uniformly mixed with the hydrogel, and the method comprises the following specific steps:
(1) dissolving a certain amount of sodium alginate in a proper amount of sterilized water for injection, filtering and sterilizing with a filter membrane, adding a certain amount of calcium chloride solution, and mixing to obtain calcium alginate hydrogel A1;
(2) subpackaging a certain amount of radioactive resin microsphere aqueous solution, and performing moist heat sterilization to obtain B1 preparation;
(3) mixing the A1 preparation and the B1 preparation with an injector before use, mixing, and standing for a while to remove air bubbles in the preparation.
For the convenience of clinical use, in another specific embodiment, the radioactive resin microsphere solution containing divalent metal ions is uniformly mixed with the alginic acid solution, and the specific steps comprise:
(1) dissolving a certain mass of sodium alginate in a proper amount of sterilized water for injection, filtering, sterilizing, packaging, and sealing to obtain a sodium alginate sterile solution A2;
(2) dispersing a certain amount of radioactive resin microspheres in a certain amount of sterile calcium chloride solution, and performing sterile subpackage to obtain a sterile radioactive resin microsphere solution containing calcium ions, wherein the dose is B2;
(3) injecting the A2 preparation into B2 preparation with syringe, mixing, and standing for a while to remove air bubbles.
In a particular embodiment, the filter is preferably a sterilizing filter with a pore size of 0.22 μm.
When the invention is used, the A1 agent and the B1 agent are preferably packaged in combination, or the A2 agent and the B2 agent are packaged in combination as a complete set product to be sent to hospitals and mixed and prepared before use.
The method of the second aspect of the present invention is a method for preparing the radioactive resin microsphere injection of the first aspect of the present invention.
In a third aspect, the present invention also provides a radioactive resin microsphere injection according to the first aspect of the present invention and the use of the radioactive resin microsphere injection prepared by the method according to the second aspect of the present invention in the preparation of a medicament for treating tumors. The tumor includes but is not limited to pancreatic cancer, liver cancer, breast cancer, prostate cancer and other solid tumors.
Further, the drug comprises a radioactive resin microsphere and a hydrogel.
Further, the medicament comprises sodium alginate and radioactive resin microspheres containing divalent metal ions.
Further research shows that the calcium alginate hydrogel can further react with calcium ions in tumor tissues to generate calcium alginate gel, and the calcium alginate gel is different from the hydrogel, has viscosity much higher than that of the hydrogel, does not have fluidity in the tissues, and is not easy to move after being fixed in the tissues. The method is beneficial to fixing the radioactive resin microsphere product in the solid tumor and not easily transferring the radioactive resin microsphere product to other tissues and organs, and can further reduce the potential safety risk of the radioactive resin microsphere product in the treatment process.
The radioactive resin microsphere injection can be directly injected and administered, and can also be injected and administered after the intervention of a puncture needle.
Specifically, when the tumor is a body surface tumor or a superficial tumor, the medicine is subjected to intralesional administration by a direct injection method; and the deep solid tumors such as pancreatic cancer, liver cancer, brain glioma and the like can be subjected to intratumoral injection administration under the guidance of a puncture needle under the guidance of ultrasonic endoscope or the guidance of ultrasonic endoscope. The solid tumor is killed and killed by local high-dose radioactive radiation, so that the tumor is treated.
The medicine can be used for local direct injection administration of the tumor, and the medicine can react with calcium ions in tissue fluid to form gel after reaching a focus part so that hydrogel gradually loses fluidity, thereby being beneficial to fixing the radioactive resin microspheres at the focus part and reducing toxic and side effects on other tissues or organs in the local radiotherapy process.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, the sodium alginate solution is prepared into the hydrogel, so that the viscosity of the sodium alginate solution is obviously reduced, the injection is not easy to generate bubbles or the bubbles are easy to discharge, the needle adaptability is improved, the dispersion uniformity of the radioactive resin microspheres in a liquid phase medium is improved, the radioactive resin microspheres are not settled in the liquid phase for a long time, the purpose of fixing the radioactive resin microspheres in the tumor is realized through further in-situ gelation of the hydrogel in the tumor, and the safety risk of clinical use of the radioactive resin microspheres is reduced on the premise of improving the distribution of the radioactive resin microspheres in the tumor.
The radioactive resin microspheres are used for preparing the medicine for treating the tumor, the medicine is directly injected and administered to the local part of the tumor, and the medicine can react with calcium ions in tissue fluid to form gel after reaching a focus part so that hydrogel gradually loses fluidity, so that the radioactive resin microspheres are favorably fixed at the focus part and the toxic and side effects to other tissues or organs in the local radiotherapy process are reduced.
The invention provides a novel and effective suspending system capable of gelling in situ in tissues for resin microspheres or radioactive resin microspheres, and well solves the problems that the radioactive resin microspheres are difficult to directly inject and the radioactive dosage can not be directly quantified through the administration volume in the administration process of the radioactive resin microspheres.
Drawings
FIG. 1 is a prior art device for perfusion administration of radioactive microspheres;
FIG. 2 is a graph showing a comparison of the suspended state of each sample after shaking and standing for 3 hours in example 11 of the present invention;
FIG. 3 is a PET scan image of SD rat liver of example 12 of the present invention after 72 hours of local injection of example 1.
Detailed Description
The following description of the embodiments of the present invention will be made with reference to the accompanying drawings. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
A process for preparing yttrium [ alpha ], [ beta ], [ alpha ], [ beta ], [ alpha ], [ beta ]90Y]A method of resin microsphere injection, the method comprising the steps of:
dissolving sodium alginate 20mg in 10ml, and sterilizingAdding 0.45g/L sterile calcium chloride solution 10ml into water for injection after passing through a 0.22 μm sterilizing filter membrane, and mixing to obtain calcium alginate hydrogel with viscosity of 16.6 mPa.S (about 20 deg.C) A1; prepared from yttrium [ 2 ]90Y]Dispersing 50mg of resin microspheres in 1ml of sterilized water for injection, packaging, and performing moist heat sterilization for 121-15 min to obtain B1 preparation; adding the A1 preparation into the B1 preparation, and mixing. No beginning sedimentation of the radioactive resin microspheres was observed within 2 hours of the injection.
Example 2
A process for preparing yttrium [ alpha ], [ beta ], [ alpha ], [ beta ], [ alpha ], [ beta ]90Y]A method of resin microsphere injection, the method comprising the steps of:
dissolving sodium alginate 20mg in 10ml sterilized water for injection, filtering with 0.22 μm sterilizing filter membrane, and packaging to obtain A2 preparation. Prepared from yttrium [ 2 ]90Y]Dispersing 100mg of resin microspheres in 1ml of sterilized water for injection containing 5mg of calcium chloride, packaging, and performing moist heat sterilization for 121-15 min to obtain B2 preparation. Adding the A2 preparation into the B2 preparation, and mixing. The injectable formulation did not observe the onset of sedimentation of the radioactive resin microspheres within 2 hours.
Example 3
Preparation of holmium [ alpha ], [ beta ] -n-beta-cyclodextrin166Ho]A method of resin microsphere injection, the method comprising the steps of:
dissolving sodium alginate 20mg in 10ml sterilized water for injection, filtering with 0.22 μm sterilizing filter membrane, and packaging to obtain A2 preparation. Holmium fortunei [ 2 ]166Ho]300mg of the resin microspheres are dispersed in 1ml of sterilized water for injection containing 5mg of calcium chloride, packaged and sterilized by moist heat for 121-15 min for later use, and the preparation is B2. Adding the A2 preparation into the B2 preparation, and mixing. The injectable formulation did not observe the onset of sedimentation of the radioactive resin microspheres within 2 hours.
Example 4
Preparation of iodine [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and a131I]A method of resin microsphere injection, the method comprising the steps of:
dissolving sodium alginate 20mg in 10ml sterilized water for injection, filtering with 0.22 μm sterilizing filter membrane, adding 0.6g/L sterile calcium chloride solution 10ml, and mixing to obtain Sargassum with viscosity of 8.4 mPa.S (about 20 deg.C)Calcium carbonate hydrogel, a1 dose. Iodine [ 2 ]131I]Dispersing 100mg of resin microspheres in 1ml of sterilized water for injection, packaging, and performing moist heat sterilization for 121-15 min to obtain B1 preparation. Adding the A1 preparation into the B1 preparation, and mixing. No beginning sedimentation of the radioactive resin microspheres was observed within 2 hours of the injection.
Example 5
Preparation of gallium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and a68Ga]A method of resin microsphere injection, the method comprising the steps of:
dissolving sodium alginate 20mg in 10ml sterilized water for injection, filtering with 0.22 μm sterilizing filter membrane, adding 0.6g/L sterile calcium chloride solution 10ml, and mixing to obtain calcium alginate hydrogel with viscosity of 8.4 mPa.S (about 20 deg.C), A1. Prepared from gallium68Ga]Dispersing 200mg of resin microspheres in 1ml of sterilized water for injection, packaging, and performing moist heat sterilization for 121-15 min to obtain B1 preparation. Adding the A1 preparation into the B1 preparation, and mixing. The injectable formulation did not observe the onset of sedimentation of the radioactive resin microspheres within 3 hours.
Example 6
Preparation of zirconium 289Zr]A method of resin microsphere injection, the method comprising the steps of:
dissolving sodium alginate 20mg in 10ml sterilized water for injection, filtering with 0.22 μm sterilizing filter membrane, adding 0.6g/L sterile calcium chloride solution 10ml, and mixing to obtain calcium alginate hydrogel with viscosity of 8.4 mPa.S (about 20 deg.C), A1. Subjecting zirconium [ 2 ]89Zr]Dispersing 25mg of resin microspheres in 1ml of sterilized water for injection, packaging, and performing moist heat sterilization for 121-15 min to obtain the B1 preparation. Adding the A1 preparation into the B1 preparation, and mixing. No settling of the radioactive resin microspheres was observed within 3 hours of the injection.
Example 7
Preparation of thorium [ alpha ], [ beta ] -and [ beta ], [ beta ] -a227Th]A method of resin microsphere injection, the method comprising the steps of:
dissolving sodium alginate 20mg in 10ml sterilized water for injection, filtering with 0.22 μm sterilizing filter membrane, adding 0.5g/L sterile calcium chloride solution 10ml, and mixing to obtain solution with viscosity of 8.0 mPa.S (about 20 deg.C)) The calcium alginate hydrogel is A1 dose. Subjecting thorium [ n ], [ n ]227Th]100mg of the resin microspheres are dispersed in 1ml of sterilized water for injection, packaged and sterilized by moist heat for 121-15 min for later use, and the preparation is B1. Adding the A1 preparation into the B1 preparation, and mixing. No settling of the radioactive resin microspheres was observed within 3 hours of the injection.
Example 8
A method for preparing a diagnosis and treatment integrated radioactive resin microsphere injection comprises the following steps:
dissolving sodium alginate 20mg in 10ml sterilized water for injection, filtering with 0.22 μm sterilizing filter membrane, adding 0.5g/L sterile calcium chloride solution 10ml, and mixing to obtain calcium alginate hydrogel with viscosity of 8.0 mPa.S (about 20 deg.C), A1. Prepared from yttrium [ 2 ]90Y]Resin microsphere of 100mg and gallium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha ] a68Ga]Dispersing 20mg of resin microspheres in 1ml of sterilized water for injection, packaging, and performing moist heat sterilization for 121-15 min to obtain B1 preparation. Adding the A1 preparation into the B1 preparation, and mixing. No beginning sedimentation of the radioactive resin microspheres was observed within 2 hours of the injection.
Other types of radioactive resin microsphere injections can be obtained by the same or similar methods and processes, and are not described herein.
Example 9
Study of injection and needle adaptability of different radioactive resin microsphere injection types in tissues:
fresh chicken breast meat was taken from the market, cut into pieces (about 3 x 2 cm), 0.5ml of the resin microsphere suspension was aspirated for injection using a 1ml syringe, the syringe was inserted vertically from the surface by a needle (depth 1 cm), and all samples were slowly injected in a single spot. Tests show that the dispersibility and suspension property of the resin microspheres in a sodium carboxymethyl cellulose solution are far better than those of a sodium alginate solution with the same concentration, so that the novel preparation and the sodium carboxymethyl cellulose as a suspending agent are subjected to comparative study. The injections in examples 1 and 2 and the chicken tissue injections of various injections of radioactive resin microspheres dispersed in 0.1% sodium carboxymethyl cellulose solution, 0.2% sodium carboxymethyl cellulose solution, 0.5% sodium carboxymethyl cellulose solution and 1.0% sodium carboxymethyl cellulose solution were sequentially administered. The results of the evaluation of needle suitability according to whether the injection was smooth and the residual condition of the resin microspheres on the needle head in the administration process are shown in table 1.
In the test process, the results show that the example 1 and the example 2 both have good needle adaptability, the administration is smooth and the administration resistance is small; the radioactive resin microsphere series dispersed by the sodium carboxymethyl cellulose solution with different concentrations also has better needle adaptability and can finish the administration; wherein, 0.5 percent and 1.0 percent of sodium carboxymethyl cellulose have larger concentration, and the injection is slightly laboursome; while 0.1% and 0.2% sodium carboxymethyl cellulose solutions both showed accidental needle blockage, but administration could be completed by adjusting the injection site.
TABLE 1. needle suitability study and data on the amount of adjuvant for different types of injections
Example 10
Research on uniformity of types of different radioactive resin microsphere injections:
10ml of each of the injections of examples 1 to 6 was placed in a 10ml measuring cylinder, 500. mu.L of each of the injections was sampled at 10, 8, 6, 4, and 2ml scales in order to measure the activity using a radioactivity meter, and 2 sampling tests were performed at each scale and averaged. The activities obtained from the samples taken on the different scales are shown in table 2.
TABLE 2. distribution uniformity test of radioactive resin microspheres for different injection formulations
The results in table 2 show that the activity measured by sampling is substantially consistent throughout examples 1-6, and the difference is within 5%, thus proving that the injection of the radioactive resin microspheres in the examples is uniform, and the radioactivity can be accurately calculated by the volume of the liquid medicine.
Example 11
Settling time study for different types of radioactive resin microsphere injection:
taking about 4ml of radioactive resin microspheres of different injection types, placing the radioactive resin microspheres into a 10ml penicillin bottle, fully shaking the radioactive resin microspheres uniformly, standing the radioactive resin microspheres, and recording the time for the resin microspheres to completely settle at the bottom of the penicillin bottle. Examples 1 and 2 were examined, and 100mg of the radioactive resin microspheres were dispersed in 10ml of a 0.1% sodium carboxymethyl cellulose solution, a 0.2% sodium carboxymethyl cellulose solution, a 0.5% sodium carboxymethyl cellulose solution, and a 1.0% sodium carboxymethyl cellulose solution, and the resulting solution was shaken thoroughly and then left to stand to record the sedimentation time. The results are shown in Table 3. The dispersion state of each injection after shaking for a certain time is shown in fig. 2, and the samples in fig. 2 correspond to the resin microspheres dispersed in 6 media in table 3 from top to bottom in sequence from left to right.
TABLE 3 sedimentation study and viscosity of the Radioactive resin microspheres in different solution media
As can be seen from the data in table 3 and fig. 2, the resin microspheres of the injection preparations of radioactive resin microspheres prepared in example 1 and example 2 are uniformly dispersed in the liquid phase medium and do not settle down for a long time, and then the stable and uniform dispersion without settling down is observed for more than 3 hours. The radioactive resin microspheres dispersed in 1.0% carboxymethyl cellulose solution have better suspension characteristics but will still settle completely in 1 hour. The radioactive resin microsphere injection has obvious advantages in the dispersion uniformity and stability of the microspheres.
Example 12
Administration and in vivo distribution studies of the radioactive resin microsphere injection:
experimental animals: SD rats 6 in half male and female, weight 300-. The administration process comprises the following steps: the rats were anesthetized and opened, and the liver lobes were fixed by gently pressing the middle lobe margin with a cotton swab. The gauze cut hole was lightly covered on the injection surface, and the radioactive microsphere injection was directly injected into the liver after being sucked by a 1ml syringe. 100uL (about 60. mu. Ci) of the resin microsphere injection of example 6 was injected, and the abdomen was closed by surgical suture. After 72 hours of administration, PET examination was carried out, the patient was placed under a scanning probe, scanned for 10 to 15 minutes, and the distribution of radioactivity was observed, and the distribution of radioactive microspheres was as shown in FIG. 3.
As can be seen in FIG. 3, zirconium [ 2 ]89Zr]The resin microspheres are injected into the liver tissue for 72 hours and then distributed in the liver tissue in a concentrated way, and the transfer of other organs and tissues does not occur. The novel injection can be intensively distributed on the organ where the injection part is positioned after being directly injected, so that the remote metastasis is not easy to occur, and the novel injection is favorable for realizing real local treatment in the tumor treatment process without damaging normal tissues, thereby ensuring the safety of patients.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (16)
1. A radioactive resin microsphere injection, which is characterized by comprising the following components in each 1ml of radioactive resin microsphere injection: 0.1-300mg of radioactive resin microspheres and 1-0.75ml of hydrogel.
2. The radioactive resin microsphere injection according to claim 1, wherein the radioactive resin microsphere has a radioactivity of 0 to 5GBq per ml of the injection.
3. The radioactive resin microsphere injection according to claim 1 or 2, wherein the radionuclide supported on the radioactive resin microsphere is any nuclide for therapeutic and/or imaging that can be stably supported on the resin microsphere, including but not limited to: yttrium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha90Y]Technetium [ alpha ]99mTc]Lutetium [ lutetium ]177Lu]Holmium [ 2 ]166Ho]Samarium [ 2 ]153Sm]Rhenium [ alpha ], [186Re]Rhenium [ alpha ], [188Re]Zirconium [ 2 ]89Zr]Gallium 268Ga]Iodine [ iodine ]131I]Iodine [ iodine ]125I]Phosphorus [ alpha ]32P]Copper [ 2 ]64Cu]Chinese medicine' Jing223Ra]Thorium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha ]227Th]2, actinium [ alpha ], [ alpha ] an225Ac]Lead 2212Pb]Any one or more of them.
4. The radioactive resin microsphere injection according to claim 1, wherein said radioactive resin microspheres include, but are not limited to: polystyrene microspheres, polyethylene microspheres, polydivinylbenzene microspheres, polylactic acid microspheres, polyglycolide-lactide microspheres, polylactide microspheres, chitosan microspheres, calcium alginate microspheres, dextran microspheres, and poly-albumin microspheres.
5. The radioactive resin microsphere injection according to claim 1, wherein the hydrogel is prepared by mixing and reacting a sodium alginate solution with divalent metal ions with good biocompatibility.
6. The radioactive resin microsphere injection according to claim 5, wherein the mass ratio of sodium alginate to divalent metal ions is 1: (0.02-0.3), preferably 1: (0.05-0.15).
7. The radioactive resin microsphere injection according to claim 5 or 6, wherein the hydrogel has a viscosity of 1 to 100 mPa.S, preferably 5 to 20 mPa.S.
8. A method for preparing a radioactive resin microsphere injection is characterized by comprising the step of uniformly mixing radioactive resin microspheres and hydrogel.
9. A method for preparing a radioactive resin microsphere injection is characterized by comprising the step of uniformly mixing a radioactive resin microsphere solution containing divalent metal ions with a sodium alginate solution.
10. A radioactive resin microsphere injection prepared by the method of claim 8 or 9.
11. Use of a radioactive resin microsphere injection according to any one of claims 1 to 7 and 10 for the preparation of a medicament for the treatment of tumors.
12. The use of claim 11, wherein the medicament comprises a radioactive resin microsphere and a hydrogel.
13. The use of claim 11, wherein the medicament comprises sodium alginate and radioactive resin microspheres containing divalent metal ions.
14. The use according to any one of claims 11 to 13, wherein, when the tumour is a superficial or superficial tumour, the medicament is administered intralesionally by direct injection, and the treatment of the tumour is effected by killing or killing solid tumours through the application of high local doses of radioactive radiation.
15. The use according to any one of claims 11 to 13, wherein, when the tumor is a deep solid tumor, the medicament is administered by intratumoral injection through needle intervention under ultrasound guidance or under ultrasound endoscope guidance, and the solid tumor is killed and killed by local high-dose radioactive radiation, so as to treat the tumor.
16. The use of claim 11, wherein the medicament is capable of gelling in situ within the tumor, thereby achieving the function of confining the radioactive resin microspheres within the tumor and avoiding damage to other tissues due to the distribution of the radioactive resin microspheres outside the tumor tissue during local radiotherapy.
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