CN114652863A - Radioactive carbon microsphere injection and preparation method and application thereof - Google Patents
Radioactive carbon microsphere injection and preparation method and application thereof Download PDFInfo
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- 239000004005 microsphere Substances 0.000 title claims abstract description 177
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title claims abstract description 171
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 171
- 230000002285 radioactive effect Effects 0.000 title claims abstract description 117
- 238000002347 injection Methods 0.000 title claims abstract description 102
- 239000007924 injection Substances 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 59
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- 238000000034 method Methods 0.000 claims description 37
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- 239000000661 sodium alginate Substances 0.000 claims description 31
- 235000010413 sodium alginate Nutrition 0.000 claims description 31
- 229940005550 sodium alginate Drugs 0.000 claims description 31
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 27
- 238000002156 mixing Methods 0.000 claims description 27
- 229910052727 yttrium Inorganic materials 0.000 claims description 14
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 14
- 229910021645 metal ion Inorganic materials 0.000 claims description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- 239000011630 iodine Substances 0.000 claims description 11
- 229910052765 Lutetium Inorganic materials 0.000 claims description 9
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 claims description 9
- 229910052726 zirconium Inorganic materials 0.000 claims description 8
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- 239000011574 phosphorus Substances 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- 229910052689 Holmium Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
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- 229910052713 technetium Inorganic materials 0.000 claims description 6
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims description 6
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 5
- 238000009826 distribution Methods 0.000 claims description 5
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- 230000002601 intratumoral effect Effects 0.000 claims description 5
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- 229910052702 rhenium Inorganic materials 0.000 claims description 5
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- 238000002604 ultrasonography Methods 0.000 claims description 5
- 238000003384 imaging method Methods 0.000 claims description 4
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 claims description 3
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- 229910052772 Samarium Inorganic materials 0.000 claims description 3
- 229910052776 Thorium Inorganic materials 0.000 claims description 3
- 229910052767 actinium Inorganic materials 0.000 claims description 3
- QQINRWTZWGJFDB-UHFFFAOYSA-N actinium atom Chemical compound [Ac] QQINRWTZWGJFDB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 2
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 claims 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 abstract description 8
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- 229940079593 drug Drugs 0.000 abstract description 6
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- 238000004062 sedimentation Methods 0.000 description 15
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 14
- 239000000648 calcium alginate Substances 0.000 description 14
- 235000010410 calcium alginate Nutrition 0.000 description 14
- 229960002681 calcium alginate Drugs 0.000 description 14
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
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- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 11
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
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- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 3
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
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- 238000005070 sampling Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
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- 239000000375 suspending agent Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
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- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- KLUYKAPZRJJIKT-UHFFFAOYSA-N lutetium Chemical compound [Lu][Lu] KLUYKAPZRJJIKT-UHFFFAOYSA-N 0.000 description 1
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- 229910001427 strontium ion Inorganic materials 0.000 description 1
- PWYYWQHXAPXYMF-UHFFFAOYSA-N strontium(2+) Chemical compound [Sr+2] PWYYWQHXAPXYMF-UHFFFAOYSA-N 0.000 description 1
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- RUQSMSKTBIPRRA-UHFFFAOYSA-N yttrium Chemical compound [Y].[Y] RUQSMSKTBIPRRA-UHFFFAOYSA-N 0.000 description 1
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
- A61K51/02—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
- A61K51/121—Solutions, i.e. homogeneous liquid formulation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Abstract
The invention belongs to the technical field of medicines, and discloses a radioactive carbon microsphere injection, a preparation method and application thereof, wherein each 1ml of the radioactive carbon microsphere injection comprises: 0.1-300mg of radioactive carbon microspheres and 1-0.8ml of hydrogel. The injection is used for preparing a medicine for treating tumors, can be directly injected into the tumors in an intervention mode, can directly determine the radioactive dose of the radioactive carbon microspheres through the administration volume, reaches hydrogel in the tumors and can form gel with calcium ions in the tumors, so that the radioactive carbon microspheres are uniformly dispersed and limited in the tumors, high-dose local radiotherapy is provided through the radioactive carbon 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 carbon microsphere injection, a preparation method and application thereof.
Background
The radioactive microsphere product applied clinically at present mainly comprises yttrium [ yttrium ], [ alpha ], and [ alpha ], and [ alpha-olefin, or [ alpha-olefin, and [ alpha-olefin, or alpha-olefin, and [ alpha-olefin, or alpha-olefin, alpha-or a mixture of a polymer, alpha-olefin, alpha-or alpha-olefin, alpha-olefin90Y]Resin microspheres SIR-Spheres (Sirtex Medical Limited, Australia) and yttrium [ [ Yttrium ] ]90Y]Glass microspheres TheraSphere (BTG, UK) and holmium [ 2 ], [ K ] in clinical trial research166Ho]Resin microspheres (QuriemSphere), which are radioactive microspheres dispersed in water for sterilization injection or 0.9 percent sodium chloride injection solution,the product can not be administrated in a mode of direct injection by an injector due to the fact that the product is deposited in a dispersion solution quickly and easy to block a needle. For the purpose of convenience of administration and radiation shielding, administration is carried out by means of an infusion administration set as shown in fig. 1, which requires a 20-60ml injection solution for washing to bring radioactive microspheres into the body along a catheter. 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 dosing of radioactive microspheres cannot be achieved depending on the volume of the drug solution delivered into the body. These limitations make SIR-Spheres and TheraSphere @onlybe used for the treatment of solid tumors with abundant arterial blood supply by means of arterial cannula interventional drug delivery, but not be used for the treatment of other solid tumors by means of intratumoral direct injection, so that the expansion of the indications is strictly limited.
The applicant has applied for a plurality of patents related to radioactive carbon microspheres, and the main technical means for improving the distribution of the microspheres is to prepare suspension injection by taking water, micromolecule aqueous solution, macromolecule aqueous solution and the like as dispersion media, improve the suspension performance of the radioactive carbon microspheres in liquid phase media by increasing the viscosity of the dispersion media, prolong the suspension time of the carbon microspheres in the solution along with the increase of the viscosity, but still cause the sedimentation of the carbon microspheres in the liquid phase media, so that the accurate calculation of the radioactive dose can not be carried out through the administration volume. Moreover, the suspension injection is also more suitable for realizing the administration of the medicine in the tumor region by an arterial infusion administration mode, and has the problems of accidental needle blockage, difficult administration and large medicine residue when the injection is directly used for injection administration by a syringe, and the aim of realizing the quantitative administration of the radioactive carbon microspheres by the volume of the liquid medicine is difficult, so the suspension injection is difficult to be directly used for the intratumoral injection administration of solid tumors.
Disclosure of Invention
In order to solve the technical problems in the background art, the invention provides a radioactive carbon microsphere injection, a preparation method and application thereof, wherein the radioactive carbon microsphere injection is low in viscosity and good in fluidity and can be directly injected for use.
In a first aspect, the invention also provides a radioactive carbon 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 radioactive carbon microspheres in water, but the carbon microspheres dispersed in the sodium alginate solution completely settle within 10 minutes. The sodium alginate and the divalent metal ions are combined to form the gel, so that the carbon microspheres can be uniformly dispersed, and the carbon microspheres can be uniformly dispersed in the gel with the optimized prescription for a long time without sedimentation.
Specifically, the radioactive carbon microsphere injection comprises the following components in each 1 ml: 0.1-300mg of radioactive carbon microspheres and 1-0.8ml of hydrogel.
Further research shows that the carbon microsphere injection can keep good fluidity when ensuring that the carbon microspheres do not settle by optimizing the proportion and the dosage of the sodium alginate and the divalent metal ions, 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 viscosity of the formed hydrogel is 5-20 mPa.S when the viscosity is 0.06-0.14. The viscosity is reduced, so that the resistance in the injection process is smaller, the needle adaptability is better, the injection becomes easier, and more importantly, the viscosity is reduced, the dispersion of the radioactive carbon microspheres in the hydrogel becomes more uniform, and the radioactive carbon 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 ion and strontium ion, preferably calcium ion.
Further, the radionuclide supported on the radioactive carbon microspheres may be any nuclide that can be stably supported on the carbon microspheres for therapeutic use and/or imaging use, 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 ], [ alpha, and [ alpha ], [ alpha186Re]Rhenium [ alpha ], [ alpha, and [ alpha ], [ alpha188Re]Zirconium [ 2 ]89Zr]Gallium 268Ga]Iodine [ iodine ]131I]Iodine [ 2 ]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 these nuclides are supported on carbon microspheres by an arbitrary method to obtain radioactive carbon microspheres.
Further research shows that the radioactive carbon microsphere injection is macroscopically homogeneous-like, namely, the radioactive dosages of the radioactive carbon microspheres contained in the injection are basically equal by taking the same volume of the injection. Therefore, the volume of the injection can be controlled to realize accurate quantitative administration of the radioactive carbon 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 when the radioactive dose of the radioactive carbon microspheres exceeds 5GBq/ml, the hydrogel undergoes radiation degradation in a short time so that the viscosity of the composition is significantly reduced and the homogeneity is destroyed.
Specifically, the radioactivity of the radioactive carbon microspheres is 0-5GBq per milliliter of radioactive carbon microspheres in the injection, so that the radioactive concentration of the radioactive carbon microsphere injection is adjustable in a certain range.
Further research shows that the radioactive carbon microsphere with the particle size of less than 1 micron can be uniformly and stably dispersed in aqueous solution of high-molecular suspending agent such as sodium carboxymethyl cellulose, hydroxyethyl starch and the like, while the particles with the particle size of 1-1000 microns cannot be uniformly and stably dispersed in 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 carbon microsphere is larger than 300 μm, it is difficult to smoothly administer the drug by direct injection, and particles having a particle size of less than 20 μm easily migrate in vivo.
Specifically, the particle size of the radioactive carbon microspheres is 1-1000 μm, preferably 20-300 μm, so that the radioactive carbon microspheres are uniformly dispersed in the hydrogel system.
Further research shows that the carbon microspheres loaded with imaging nuclide, therapeutic nuclide or one or more radionuclides simultaneously or radioactive carbon microspheres prepared by different methods can be uniformly dispersed in the calcium alginate hydrogel.
Specifically, the radioactive carbon microsphere includes but is not limited to: yttrium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha90Y]Carbon microsphere, technetium [ alpha ]99mTc]Carbon microsphere, lutetium [ Lu ]177Lu]Carbon microsphere, holmium [ 2 ]166Ho]Carbon microsphere, samarium [ alpha ], [ beta ], [ alpha ], [ beta ] -a153Sm]Carbon microsphere, rhenium [ alpha ], [ beta ] a186Re]Carbon microsphere, rhenium [ alpha ], [ beta ] a188Re]Carbon microsphere, zirconium [ alpha ], [ beta ] -a89Zr]Carbon microsphere, gallium [ alpha ], [ beta ]68Ga]Carbon microsphere, iodine [ 2 ]131I]Carbon microsphere, iodine [ 2 ]125I]Carbon microsphere, phosphorus [ alpha ], [ beta ] -a32P]Carbon microsphere, copper [ alpha ], [ beta ], [ alpha ], [ beta ], [ alpha ], [ beta ] -a64Cu]Carbon microsphere, radium [ 2 ]223Ra]Carbon microsphere, thorium [ alpha ], [ beta ] -a227Th]Carbon microsphere, actinium [ alpha ], [ beta ] -n225Ac]Carbon microsphere, lead [ alpha ], [ beta ] -a212Pb]Any one or more of carbon microspheres. That is, the present invention realizes a hydrogel system in which radioactive carbon microspheres suitable for therapy and/or imaging are uniformly dispersed, the hydrogel system being simultaneously suitable for one or more radioactive carbon microspheres.
In a second aspect, the present invention also provides a method for preparing a radioactive carbon microsphere injection, which comprises the following two preparation methods:
in one embodiment, the radioactive carbon microspheres are directly and uniformly mixed with the hydrogel, and the specific steps comprise:
(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 carbon microsphere aqueous solution, and performing damp-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 carbon microsphere solution containing divalent metal ions is uniformly mixed with the sodium alginate solution, and the specific steps comprise:
(1) dissolving a certain mass of sodium alginate in a proper amount of sterilized water for injection, filtering for sterilization, packaging, and sealing to obtain a sterile solution A2;
(2) dispersing a certain amount of radioactive carbon microspheres in a certain amount of calcium chloride solution, subpackaging, and carrying out damp-heat sterilization for 121-15 minutes to obtain a sterile radioactive carbon 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 producing the radioactive carbon microsphere injection of the first aspect of the present invention.
In a third aspect, the present invention also provides a radioactive carbon microsphere injection according to the first aspect of the present invention and an application of the radioactive carbon microsphere injection prepared by the method according to the second aspect of the present invention in preparing 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 radioactive carbon microspheres and hydrogel.
Further, the medicament comprises sodium alginate and radioactive carbon 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 carbon microsphere product in the solid tumor and not easily transferring to other tissues and organs, and can further reduce the potential safety risk of the radioactive carbon microsphere product in the treatment process.
The radioactive carbon 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 carbon 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 needle adaptability is improved, the dispersion uniformity of the radioactive carbon microspheres in a liquid phase medium is improved, the radioactive carbon microspheres are prevented from settling in a liquid phase for a long time, the purpose of fixing the radioactive carbon microspheres in a tumor is realized through further in-situ gelation of the hydrogel in the tumor, the safety risk of clinical use of the radioactive carbon microspheres is reduced on the premise of improving the distribution of the radioactive carbon microspheres in the tumor, and the application prospect is good.
The radioactive carbon microsphere is used for preparing a medicine for treating tumors, the medicine is locally and directly injected and administered to the tumors, 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 carbon microsphere is favorably fixed at the focus part and toxic and side effects on other tissues or organs in a local radiotherapy process are reduced.
The invention well solves the problems that the radioactive carbon 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 carbon 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 dispersion state of each sample after shaking and standing for 10 minutes in example 15 of the present invention;
FIGS. 3 to 6 are ultrasonic images of hepatic solid tumors before administration to a control group, after administration to a control group, before administration to an administration group, and after administration to an administration group, respectively, in example 16 of the present invention.
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 for preparing a carbon microsphere injection, which comprises the following steps:
dissolving sodium alginate 20mg in 10ml sterilized water for injection, filtering with 0.22 μm sterilizing filter membrane, adding 0.45g/L sterile calcium chloride solution 10ml, 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 100mg of carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 2
A process for preparing yttrium [ alpha ], [ beta ], [ alpha ], [ beta ], [ alpha ], [ beta ]90Y]A method of carbon 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 0.7g/L sterile calcium chloride solution 10ml, and mixing to obtain calcium alginate hydrogel with viscosity of 14.3 mPa.S (about 20 deg.C) A1; prepared from yttrium [ 2 ]90Y]Dispersing 100mg of carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 3
A process for preparing yttrium [ alpha ], [ beta ], [ alpha ], [ beta ], [ alpha ], [ beta ]90Y]A method of carbon 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 carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 4
Preparation of yttrium [ 2 ]90Y]A method of carbon 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 300mg of carbon 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 B2 preparation, and mixing. The injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 3 hours.
Example 5
Preparation of lutetium [ Lu ] [ Lu ]177Lu]A method of carbon microsphere injection, the method comprising the steps of:
collecting seaweedDissolving sodium 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. Lutetium [ lutetium ], [ solution of lutetium ], [ solution of lutetium ], [ solution of a [ solution of lutetium ]177Lu]Dispersing 100mg of carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 6
Preparation of iodine [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and a131I]A method of carbon 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. Iodine [ 2 ]131I]Dispersing 200mg of carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 7
Preparation of zirconium 289Zr]A method of carbon 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. Zirconium 289Zr]Dispersing 5mg of carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 8
A method for preparing a diagnosis and treatment integrated radioactive carbon microsphere injection comprises the following steps:
dissolving sodium alginate 20mg in10ml of sterilized water for injection is filtered through a 0.22 mu m sterilizing filter membrane, 10ml of 0.5g/L sterile calcium chloride solution is added, and calcium alginate hydrogel with the viscosity of 8.0mPa & S (about 20 ℃) is obtained after even mixing, namely A1 agent. Zirconium 289Zr]Carbon microsphere of 10mg and yttrium90Y]Dispersing 100mg of carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 9
Preparation of gallium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and a68Ga]And holmium 2166Ho]A method of carbon 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 gallium68Ga]Carbon microsphere 50mg and holmium [ 2 ]166Ho]Dispersing 50mg of carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 10
Preparation of technetium [ alpha ], [ alpha ]99mTc]Carbon microsphere and phosphorus [ alpha ], [ beta ] -a32P]A method of carbon 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. Technetium [ n ]99mTc]Carbon microsphere 30mg and phosphorus [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha ], [ alpha ] a32P]Dispersing 70mg of carbon microspheres in 1ml of sterilized water for injection containing 6mg of calcium chloride, packaging, and performing moist heat sterilization for 121-15 min to obtain B2 preparation. Adding the A2 preparation into B2 preparation, and mixing. The injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Example 11
A method for preparing radium [ alpha ], [ alpha ]223Ra]Carbon microsphere and technetium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha ], [ alpha ] a99mTc]A method for preparing a carbon microsphere injection, which comprises the following steps:
taking alginic acidDissolving sodium 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 A1. Will be radium 2223Ra]Carbon microsphere 10mg and technetium99mTc]Dispersing 5mg of carbon 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 injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 10 hours.
Example 12
A process for preparing phosphorus [ alpha ], [ alpha ] and a32P]Carbon microsphere zirconium (2)89Zr]A method for preparing a carbon microsphere 120mg injection, which comprises the following steps:
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. Phosphorus [ alpha ], [ alpha ] and a32P]Carbon microsphere 180mg and zirconium [ 2 ]89Zr]Dispersing 120mg of carbon 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 B1 preparation, and mixing. The injection did not observe the onset of sedimentation of the radioactive carbon microspheres within 5 hours.
Other types of radioactive carbon microsphere injections can be obtained by the same or similar methods and processes as described above, and are not described herein.
Example 13
The injection and needle suitability of different radioactive carbon microsphere injection types in tissues were studied:
commercial fresh chicken breast was taken, diced (about 3 x 2 cm), 0.5ml of the suspension of carbon microspheres was aspirated for injection using a 1ml syringe, the syringe was inserted vertically from the surface (depth 1 cm), and all samples were injected slowly in a single spot. The injections in examples 1, 2 and 3 and the chicken tissues in which the radioactive carbon microspheres are dispersed in sterilized injection water, a 3% hydroxyethyl starch solution, a 0.2% sodium alginate solution and a 0.2% sodium carboxymethyl cellulose solution are sequentially injected and administered. The results of the evaluation of the needle suitability according to whether the injection was smooth and the carbon microspheres remained on the needle during the administration are shown in Table 1.
TABLE 1. needle-appropriate study of different types of injections
Example 14
Study on uniformity of different radioactive carbon microsphere injection types:
the number of radioactive carbon microspheres in a unit volume of the dispersion was measured by using a Countstar counter. 10ml of each of the solutions of example 1, example 2 and example 3 was placed in a 10ml measuring cylinder, 20. mu.L of each solution was sampled at 10, 8, 6, 4 and 2ml scales in sequence, and the number of particles was measured using an automatic cytometer, and 3 sampling tests were performed at each scale and averaged. The results of the counting are shown in table 2, and the results show that the radioactive carbon microspheres are uniformly dispersed in the hydrogel.
TABLE 2. distribution uniformity test of radioactive carbon microspheres for different injection formulations
10ml of each of the injections of example 1, example 2 and example 3 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 sequence, and activity measurement was performed 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 3. The results in Table 3 show that the activity of the samples taken throughout examples 1-3 is substantially consistent, demonstrating that the injectate itself is homogeneous and that accurate calculation of radioactivity can be made by volume of the drug solution.
TABLE 3. distribution uniformity test of radioactive carbon microspheres for different injection formulations
Example 15
Settling time study of different radioactive carbon microsphere injection types:
taking about 8ml of radioactive carbon microspheres of different injection types, placing the radioactive carbon microspheres into a penicillin bottle of 10ml, fully shaking up, standing, and recording the time for the radioactive carbon microspheres to completely settle at the bottom of the penicillin bottle. Examples 1-3 were studied separately and 100mg of radioactive carbon microspheres were dispersed in 10ml of 0.2% sodium alginate solution, sterile water for injection, 0.9% sodium chloride injection, 3% hydroxyethyl starch solution, 0.2% sodium carboxymethyl cellulose solution, shaken well and then left to stand, and the sedimentation time was recorded. The results are shown in Table 4. The dispersion state ratio of each injection after shaking up and standing for 10 minutes is shown in FIG. 2, and the samples in FIG. 2 correspond to the dispersion medium from top to bottom 7 in Table 4 sequentially from left to right.
TABLE 4 time of settling of radioactive carbon microspheres on the bottom of the bottle in different solution media
As is clear from the data in table 4 and fig. 2, the radioactive carbon microsphere injection prepared in examples 1 to 3 was uniform in dispersion of the carbon microspheres in the liquid medium and did not settle for a long period of time, the time for stable and uniform dispersion without settling was more than 5 hours, and the radioactive carbon microspheres settled at the bottom of the bottle within 20 minutes in all of the other four formulations.
Example 16
Research on treatment of liver solid tumor by radioactive carbon microsphere injection:
the injection of example 1 was used to treat liver solid tumors in New Zealand rabbits, and the location and size of the liver tumors in the New Zealand rabbits were determined by ultrasound. The volume of liver tumor in the group administered before administration was about 4.9cm3The volume of the injection liquid is 8 percent of the tumor volume, puncture needle injection administration is carried out under the guidance of ultrasound, 0.4ml of the injection in the embodiment 1 is taken out by using an injector for injection administration after the administration position is determined, a certain volume of normal saline is administered to a control group, the treatment effect is evaluated by using ultrasound 1 week after the administration is finished, and the ultrasound before and after the treatment is carried outThe images are shown in fig. 3-6, and fig. 3-6 are ultrasonic images of liver solid tumor treatment before control group administration, after control group administration, before administration group administration and after administration group administration, respectively.
As can be seen from the results of the study in conjunction with FIGS. 3-6, the tumor volume before administration was about 2.6cm in the control group3Tumor volume was 8.9cm after 5 days3(ii) a The dose of the administration group was 4.9cm before administration3The tumor volume was 3.7cm after 5 days of administration3. The treated group of tumors stops growing and has reduced volume, and the novel injection shows application prospect in treating solid tumors.
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 (15)
1. A radioactive carbon microsphere injection, which is characterized in that each 1ml of the radioactive carbon microsphere injection comprises: 0.1-300mg of radioactive carbon microspheres and 1-0.8ml of hydrogel.
2. The radioactive carbon microsphere injection according to claim 1, wherein the radioactive carbon microsphere has a radioactivity of 0 to 5GBq per ml of the injection.
3. The radiocarbon microsphere injection of claim 1 or 2, where the radionuclide supported on the radiocarbon microsphere is any radionuclide that can be stably supported on the carbon microsphere for therapeutic and/or imaging applications including but not limited to: yttrium [ alpha ], [ alpha ] and [ alpha ], [ alpha ] and [ alpha90Y]Technetium [ 2 ]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]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.
4. The radioactive carbon 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.
5. The radioactive carbon microsphere injection according to claim 4, wherein the mass ratio of sodium alginate to divalent metal ions is 1: (0.02-0.3), preferably 1: (0.05-0.15).
6. The radioactive carbon microsphere injection according to claim 4 or 5, wherein the hydrogel has a viscosity of 1 to 100 mPa.S, preferably 5 to 20 mPa.S.
7. A method for preparing a radioactive carbon microsphere injection, which is characterized by comprising the step of uniformly mixing radioactive carbon microspheres with hydrogel.
8. A method for preparing a radioactive carbon microsphere injection is characterized by comprising the step of uniformly mixing a radioactive carbon microsphere solution containing divalent metal ions with a sodium alginate solution.
9. A radioactive carbon microsphere injection prepared by the method of claim 7 or 8.
10. Use of the radioactive carbon microsphere injection as claimed in any one of claims 1 to 6 and 9 in the preparation of a medicament for treating tumors.
11. The use of claim 10, wherein the medicament comprises radioactive carbon microspheres and a hydrogel.
12. The use of claim 10, wherein the medicament comprises sodium alginate and radioactive carbon microspheres containing divalent metal ions.
13. The use of any one of claims 10-12, wherein when the tumor is a superficial or superficial tumor, the medicament is administered intralesionally by direct injection, and the treatment of the tumor is achieved by killing and killing solid tumors with high local doses of radioactive radiation.
14. The use according to any one of claims 10 to 12, wherein when the tumor is a deep solid tumor, the medicament is administered by intratumoral injection under the guidance of an ultrasound-guided puncture needle or an ultrasound endoscope, and the tumor is treated by killing and killing the solid tumor through local high-dose radioactive radiation.
15. The use of claim 10, wherein the medicament is capable of gelling in situ within the tumour, to achieve a function of confining the radioactive carbon microspheres within the tumour, to avoid damage to other tissues due to distribution of the radioactive carbon microspheres outside the tumour tissue during local radiotherapy.
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| CN101283978A (en) * | 2008-05-30 | 2008-10-15 | 济南基福医药科技有限公司 | Anticancer sustained-release gel injection containing platinum compound |
| CN105854805B (en) * | 2016-05-31 | 2018-12-25 | 浙江大学 | A kind of modification biological carbon microspheres and its preparation method and application |
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| WO2005087274A1 (en) * | 2004-03-05 | 2005-09-22 | Xl Sci-Tech, Inc. | Particulate materials and compositions for radio therapy |
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