CN117618631A - Developing embolism microsphere and preparation method thereof - Google Patents
Developing embolism microsphere and preparation method thereof Download PDFInfo
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- CN117618631A CN117618631A CN202311685221.2A CN202311685221A CN117618631A CN 117618631 A CN117618631 A CN 117618631A CN 202311685221 A CN202311685221 A CN 202311685221A CN 117618631 A CN117618631 A CN 117618631A
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- 239000004005 microsphere Substances 0.000 title claims abstract description 84
- 208000005189 Embolism Diseases 0.000 title abstract description 26
- 238000002360 preparation method Methods 0.000 title description 9
- 230000003073 embolic effect Effects 0.000 claims abstract description 61
- 239000002872 contrast media Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims abstract description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 12
- 239000011630 iodine Substances 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 10
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- 239000003054 catalyst Substances 0.000 claims description 7
- 229960001025 iohexol Drugs 0.000 claims description 7
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
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- 230000035484 reaction time Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- DVKJHBMWWAPEIU-UHFFFAOYSA-N toluene 2,4-diisocyanate Chemical compound CC1=CC=C(N=C=O)C=C1N=C=O DVKJHBMWWAPEIU-UHFFFAOYSA-N 0.000 claims description 4
- 229920001661 Chitosan Polymers 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 125000005442 diisocyanate group Chemical group 0.000 claims description 3
- -1 iobiziol Chemical compound 0.000 claims description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](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]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- RTTZISZSHSCFRH-UHFFFAOYSA-N 1,3-bis(isocyanatomethyl)benzene Chemical compound O=C=NCC1=CC=CC(CN=C=O)=C1 RTTZISZSHSCFRH-UHFFFAOYSA-N 0.000 claims description 2
- FWWWRCRHNMOYQY-UHFFFAOYSA-N 1,5-diisocyanato-2,4-dimethylbenzene Chemical compound CC1=CC(C)=C(N=C=O)C=C1N=C=O FWWWRCRHNMOYQY-UHFFFAOYSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- XUHXFSYUBXNTHU-UHFFFAOYSA-N Iotrolan Chemical compound IC=1C(C(=O)NC(CO)C(O)CO)=C(I)C(C(=O)NC(CO)C(O)CO)=C(I)C=1N(C)C(=O)CC(=O)N(C)C1=C(I)C(C(=O)NC(CO)C(O)CO)=C(I)C(C(=O)NC(CO)C(O)CO)=C1I XUHXFSYUBXNTHU-UHFFFAOYSA-N 0.000 claims description 2
- AMDBBAQNWSUWGN-UHFFFAOYSA-N Ioversol Chemical compound OCCN(C(=O)CO)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I AMDBBAQNWSUWGN-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
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- 150000004781 alginic acids Chemical class 0.000 claims description 2
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- 229960004359 iodixanol Drugs 0.000 claims description 2
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 claims description 2
- 229960002603 iopromide Drugs 0.000 claims description 2
- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 claims description 2
- 229960003182 iotrolan Drugs 0.000 claims description 2
- 229960004537 ioversol Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 239000004632 polycaprolactone Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 239000004626 polylactic acid Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 description 8
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- 208000014018 liver neoplasm Diseases 0.000 description 7
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- 239000003814 drug Substances 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000003431 cross linking reagent Substances 0.000 description 3
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- 238000005516 engineering process Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 238000012412 chemical coupling Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 150000000921 Gadolinium Chemical class 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- 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 1
- 201000011510 cancer Diseases 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000010102 embolization Effects 0.000 description 1
- 238000010556 emulsion polymerization method Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000008424 iodobenzenes Chemical class 0.000 description 1
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- 238000011068 loading method Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
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- 230000000379 polymerizing effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-UHFFFAOYSA-N 0.000 description 1
- 239000002331 radioactive microsphere Substances 0.000 description 1
- 238000011297 radiofrequency ablation treatment Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses a developing embolism microsphere, wherein an iodine-containing contrast agent is grafted on the surface of the embolism microsphere through isocyanate groups. Its preparing process is also disclosed. The developing embolism microsphere provided by the invention has an X-ray absorption function, can directly observe the embolic agent position in an operation, judge the embolism end point and reduce the risk of ectopic embolism.
Description
Technical Field
The invention relates to a developing embolism microsphere and a preparation method thereof, belonging to the technical field of medical appliances.
Background
In the disease mortality ranking of China, tumors are always in the front, and researches on tumor diagnosis and treatment are widely focused. Wherein liver cancer is one of the cancer types with highest incidence rate, and 90.56 ten thousand of new liver cancers worldwide take place in 2021, 46.6 ten thousand of new liver cancers in China account for 55% of the world according to statistics. The liver cancer has high death rate, becomes the third most serious cause of cancer death, and seriously threatens the lives and health of the national people. Currently, common methods for early treatment of liver cancer include surgical excision, radiofrequency ablation treatment, chemotherapy, radiotherapy and the like. However, most liver cancer patients are in middle and late stages in diagnosis, and only 20% -35% of patients can be subjected to excision surgery according to statistics. Arterial embolism Treatment (TAE) through a catheter is considered as a first choice method for palliative treatment of patients with middle and late liver cancer, namely, under the monitoring of imaging equipment, embolic materials are injected into blood supply arterial blood vessels of tumor tissues through the catheter, so that the 'hunger' of blood supply to tumors is blocked, the growth of the tumors is inhibited, and the tumors can be killed by locally releasing high-concentration radiotherapy and chemotherapy drugs.
There are many embolic materials available for embolic therapy, early gelatin sponge particles, iodinated oil, etc., and as materials develop and progress, microspheres become the primary choice of embolic materials due to their unique spherical fluidity. The common embolic materials in the microspheres comprise polyvinyl alcohol (PVA), polylactic acid-glycolic acid copolymer (PLGA), calcium alginate, chitosan and the like, and the materials have good biocompatibility, are nontoxic, low in cost and rich in source, so that the embolic materials are widely applied in the biomedical field. There are many embolic microspheres in the market such as blank microspheres, drug-loaded microspheres, radioactive microspheres, degradable microspheres, etc. The drug-loaded microsphere has the advantage of being capable of loading various drugs, plays roles of embolism and drugs, such as Callispheres of Hengrui corporation, foreign DC Bead, embosphere, hepasphere and the like, and has wide application prospect. However, in clinical use, in order to achieve traceability of embolic microspheres, it is generally required that embolic microspheres have X-ray absorbability (contrast capability), and at the same time, most of the microspheres on the market cannot be developed by themselves, are difficult to accurately locate in surgery, and influence investigation of embolic effects to some extent. Therefore, the development and preparation of the embolic microsphere capable of self-imaging have important research significance and market value.
Chinese patent No. 115845117A discloses an embolic agent, which is prepared by uniformly mixing gel components and inorganic components to obtain mixed gel, and simultaneously adding microspheres and a developer to uniformly mix, wherein the obtained embolic microspheres have a developing effect, and no additional developer is required to be added in use; chinese patent No. 115770321A discloses an embolism microsphere and a preparation method thereof, wherein an aqueous phase solution and an oil phase solution are mixed to form an oil-in-water forward suspension polymerization system, a pore-forming agent is a mixed reagent of toluene, liquid wax and n-heptane, the microsphere and a sodium sulfate solution are stirred and dispersed in water, and a barium chloride solution is added for stirring and dispersing, so that the developing embolism microsphere loaded with barium sulfate is obtained. The technology has a certain risk of dissolution of the contrast agent by a method of physically mixing the contrast agent with the microspheres, and can influence the therapeutic and prognostic effects.
Chinese patent No. 115590824A discloses a polyvinyl alcohol embolism microsphere with developer, its preparation method and application, firstly, diethyl triamine pentaacetic anhydride and methacrylic acid-2-amino ethyl ester are mixed to produce amidation, the reaction is carried out to produce DTPA connected with two methacrylic acid-2-amino ethyl esters, then chelating reaction is carried out with gadolinium salt, crosslinking agent with developing element is prepared, then emulsion polymerization method or microfluidic method is used to prepare polyvinyl alcohol microsphere, and the crosslinking agent is used to crosslink, thus preparing polyvinyl alcohol embolism microsphere with developing effect and drug carrying capability under MRI. The technique is magnetic resonance imaging and does not belong to the X-ray imaging technique.
The Chinese patent No. 115590824A discloses a radiopaque developing embolism microsphere and a preparation method thereof, wherein the radiopaque developing embolism microsphere with more stable structure is obtained by covalent bond coupling of an iodine-containing developer, a polyvinyl alcohol microsphere and a polymer microsphere of a water-soluble polymer with a sulfonic group; chinese patent No. CN115487342a discloses an self-developing absorbable embolic microsphere and a method for preparing the same, wherein a developable iodobenzene compound is introduced into a gelatin sponge embolic microsphere by chemical bonding, providing an X-ray impermeable self-developing absorbable embolic microsphere; chinese patent No. CN114377190a discloses a developable embolic microsphere and a method for preparing the same, wherein the embolic microsphere is formed by polymerizing biodegradable functionalized macromolecules through an initiator, a crosslinking agent and a contrast agent, and can be developed under the irradiation of X-rays; chinese patent No. 114057600A discloses an X-ray developable molecule, drug-carrying embolism microsphere and a preparation method thereof, wherein the X-ray developable molecule with double bond is obtained by reacting an iodobenzene derivative containing amino or hydroxyl with acrylic anhydride, and the drug-carrying embolism microsphere capable of being developed by X-ray is prepared. The technology is applied to embolic microspheres by self-designing or preparing iodine-containing compounds, and does not involve direct chemical coupling or surface modification of commercial contrast agents such as iohexol and the like.
The contrast agent represented by iohexol is a commercial X-ray developer for intrathecal injection, is widely used for contrast examination and interventional operation of cardiovascular, arteriovenous, biliary tract, urinary tract, intracranial, vertebral canal and the like, and has lower osmotic pressure and toxicity. Unlike available patent technology, the present invention provides one simple and efficient method for the coupling modification of embolic microsphere as the contrast agent. Specifically, the surface of the embolic microsphere is modified by diisocyanate reagents, the surface of the embolic microsphere is covalently coupled with isocyanate groups, and the surface of the embolic microsphere is further covalently reacted with hydroxyl groups on the contrast agent, so that the contrast agent is covalently modified on the surface of the embolic microsphere. Imparting development properties during use thereof, thereby avoiding or reducing the risk of ectopic embolization of the embolizing microspheres during use. More particularly, a method and related process for covalently coupling an X-ray contrast agent to embolic microspheres is provided.
Disclosure of Invention
The invention aims to realize developable embolic microspheres by using a method of grafting a contrast agent on the surface.
The aim of the invention is achieved by the following technical scheme:
a developing embolic microsphere is prepared by grafting iodine-containing contrast agent on the surface of embolic microsphere via isocyanate group.
Preferably, the isocyanate groups are chemically coupled to the hydroxyl groups of the iodine-containing contrast agent.
Preferably, the isocyanate groups are derived from toluene-2, 4-diisocyanate, m-xylylene diisocyanate or 1, 3-xylylene diisocyanate.
Preferably, the iodine-containing contrast agent is selected from iopromide, diatrizamine, iobenzene hexaol, iotrolan, iobiziol, iodixanol, ioversol, iohexol.
Preferably, the embolic microspheres are made of polylactic acid, polycaprolactone, polyglycolic acid, polyethylene glycol, polyacrylate, polyvinyl alcohol and copolymers thereof, cellulose, alginic acid and salts thereof, hyaluronic acid and salts thereof, chitosan, dextran or gelatin.
The invention also discloses a preparation method of the developing embolism microsphere, which comprises the following steps:
(1) Immersing the embolic microsphere in a solution of diisocyanate reagent, performing grafting reaction under the action of a catalyst, and modifying isocyanate groups on the surface of the embolic microsphere in a covalent reaction mode;
(2) Immersing the embolic microsphere modified with the isocyanate group in a solution of an iodine-containing contrast agent, performing grafting reaction under the action of a catalyst, and performing chemical coupling on the isocyanate group and hydroxyl of the iodine-containing contrast agent to obtain the embolic microsphere with the surface covalently modified contrast agent.
Preferably, the catalyst in steps (1) and (2) is triethylamine.
Preferably, the solvent in the step (1) is an organic solvent selected from N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene and chloroform; the solvent in the step (2) is water.
Preferably, the reaction temperature in the step (1) is 40-90 ℃ and the reaction time is 0.5-4 h.
Preferably, the reaction temperature in the step (2) is 40-90 ℃ and the reaction time is 0.5-4 h.
The beneficial effects are that: the developing embolism microsphere provided by the invention has an X-ray absorption function, can directly observe the embolic agent position in an operation, judge the embolism end point and reduce the risk of ectopic embolism.
Drawings
FIG. 1 is a chemical structural formula of iohexol (iohexol).
FIG. 2 is a schematic diagram of a process for preparing a developed embolic microsphere.
FIG. 3 is a schematic diagram of the structure of a developed embolic microsphere.
The specific implementation method comprises the following steps:
the present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and the terms used herein in this description of this invention are for the purpose of describing particular embodiments only and are not intended to be limiting of this invention.
The materials or instruments used in the following examples, if not specifically described, were available from conventional commercial sources.
Example 1
Taking 10mL of embolic microspheres, namely polyvinyl alcohol (PVA), repeatedly ultrasonically cleaning the embolic microspheres by ethanol and deionized water for three times, taking out the embolic microspheres, immersing the embolic microspheres in 20mL of toluene solution of toluene-2, 4-diisocyanate (TDI) (volume concentration is 10%), adding triethylamine as a catalyst (volume concentration is 5%), treating for 1h at 60 ℃ for grafting reaction, taking out the embolic microspheres, repeatedly flushing the embolic microspheres by toluene for 3 times, and then placing the embolic microspheres in 20mL of aqueous solution of iohexol (chemical structural formula is shown in figure 1), wherein the concentration is 10wt% and the volume concentration of triethylamine is 5%, and treating for 2h at 40 ℃. And after the reaction is finished, taking out the embolism microsphere, washing the embolism microsphere for 3 times by pure water, and immersing the embolism microsphere in the pure water or preserving the embolism microsphere by drying. The obtained embolic microsphere with development performance is characterized by having an X-ray absorption function. The reaction process is shown in figure 2, and the structure of the obtained embolic microsphere is shown in figure 3.
The embolic microsphere with the development function can be developed under the irradiation of X rays, can realize the detection and the tracking of the embolic microsphere in a human body, and is beneficial to the tracking of the degree and the range of embolism after the embolic treatment.
The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the present invention and to implement the same, but are not intended to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.
Claims (10)
1. A developing embolic microsphere is characterized in that an iodine-containing contrast agent is grafted on the surface of the embolic microsphere through isocyanate groups.
2. The developed embolic microsphere according to claim 1, wherein the isocyanate groups are chemically coupled to hydroxyl groups of the iodine-containing contrast agent.
3. The developing embolic microsphere according to claim 1, wherein the isocyanate groups are derived from toluene-2, 4-diisocyanate, m-xylylene diisocyanate or 1, 3-xylylene diisocyanate.
4. The developing embolic microsphere according to claim 1, wherein the iodine-containing contrast agent is selected from the group consisting of iopromide, diatrizosamine, iobenzene hexaol, iotrolan, iobiziol, iodixanol, ioversol, iohexol.
5. The developing embolic microsphere according to claim 1, wherein the embolic microsphere is made of polylactic acid, polycaprolactone, polyglycolic acid, polyethylene glycol, polyacrylate, polyvinyl alcohol and copolymers thereof, cellulose, alginic acid and salts thereof, hyaluronic acid and salts thereof, chitosan, dextran or gelatin.
6. The method for preparing the developing embolic microsphere according to any one of claims 1 to 5, comprising the steps of:
(1) Immersing the embolic microspheres in a solution of diisocyanate reagents, and performing grafting reaction under the action of a catalyst to obtain embolic microspheres modified with isocyanate groups;
(2) Immersing the embolic microsphere modified with isocyanate groups in a solution of an iodine-containing contrast agent, and performing grafting reaction under the action of a catalyst to obtain the embolic microsphere with the surface covalently modified contrast agent.
7. The process according to claim 6, wherein the catalyst in each of the steps (1) and (2) is triethylamine.
8. The process according to claim 7, wherein the solvent in the step (1) is an organic solvent selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene and chloroform;
the solvent in the step (2) is water.
9. The process according to claim 7, wherein the reaction temperature in the step (1) is 40 to 90℃and the reaction time is 0.5 to 4 hours.
10. The process according to claim 7, wherein the reaction temperature in the step (2) is 40 to 90℃and the reaction time is 0.5 to 4 hours.
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| CN202311685221.2A CN117618631A (en) | 2023-12-11 | 2023-12-11 | Developing embolism microsphere and preparation method thereof |
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| CN202311685221.2A CN117618631A (en) | 2023-12-11 | 2023-12-11 | Developing embolism microsphere and preparation method thereof |
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