CN101513542B - Method for preparing iodic liquid embolic agent capable of self-developing for long-time - Google Patents
Method for preparing iodic liquid embolic agent capable of self-developing for long-time Download PDFInfo
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- CN101513542B CN101513542B CN2009100200420A CN200910020042A CN101513542B CN 101513542 B CN101513542 B CN 101513542B CN 2009100200420 A CN2009100200420 A CN 2009100200420A CN 200910020042 A CN200910020042 A CN 200910020042A CN 101513542 B CN101513542 B CN 101513542B
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Abstract
The invention provides a method for preparing an iodic liquid embolic agent capable of long-time self-developing. Water-soluble polyvinyl alcohol (PVA) is added with pyridine to be stirred and evaporated for removing the pyridine. Residual reactant is dehumidified and dissolved in dimethyl sulphoxide (DMSO) organic solvent and then is added with solution of iodic compound and dichloromethane and added with triethylamine; and an obtained iodic product (I-PVA) is poured into a mixture of butyl ether and acetone to be deposited and separated. The iodic product is washed in water, is dried and then is confected into the liquid embolic agent by the dimethyl sulphoxide or N-methyl-ketopyrrolidine organic solvent. The liquid embolic agent prepared by the invention is injectable and can develop under X-ray for a long time. When contacting with blood, the organic solvent diffuses fast for depositing and separating solid to take embolic effect. The embolic agent can be used for embolotherapy of cerebral arteriovenous malformation, tumour and other vascular disease.
Description
Technical field
The present invention relates to a kind of medical use liquid suppository, is a kind of method for preparing that contains the iodine liquid embolic agent capable of long-time self-developing specifically.
Background technology
We know, in the intervention embolization operation, suppository plays an important role, and clinical widely used liquid embolizing agent is the material with X-ray opaque at present, and like the tantalum powder, contain the chemical compound of iodine, hybrid mode adds in the polymer.
Patent of invention ZL021344116 discloses a kind of ending vascular embolism preparation, and this suppository metal core is connected to form nutty structure through binding agent.Produce development effect through metal, it is visual good to have under the X-ray; Proportion is moderate, is convenient in blood vessel, form thrombosis, is difficult for backflowing, and has effectively avoided the mistake bolt.Patent of invention ZL 2006101456411 discloses a kind of non-viscous medical use liquid embolic agent; By mass/volume percent is that 3.0%～25% water-insoluble organic polymer and the mass/volume percent that are dissolved in the organic solvent is that 15%～40% medical development agent combines; The vinyl that wherein contains 30%～50% mole percent in the organic polymer; And contain ethanol in the organic solvent, ethanol is 5～35% in the percentage by volume of suppository.This liquid embolizing agent toxicity is little, can directly inject the thromboembolism position, and used developing material tantalum powder adds with hybrid mode.ZL 2004100378365 discloses a kind of responsive to temperature type liquid embolizing agent, and developing agent wherein adds provisional development with the hybrid mode that contains iodine compound.U.S.'s product onyx liquid embolizing agent also is that employing tantalum powder is a developing agent, adds through mixing.
Above-mentioned prior art is because tantalum powder or to contain iodine compound be not to adopt chemical method to be attached on the polymer backbone, tend to take place in the conduit deposition or around tissue slowly discharge, and lose the development effect.Temporary development can increase workload and expense that postoperative is checked, causes more burdens to the patient, when Clinical Follow-up, possibly become main defective.
Summary of the invention
Technical problem to be solved by this invention is the deficiency that overcomes temporary development in the above-mentioned prior art; Provide a kind of preparation simple; The iodine compound that contains that adds is attached on the polymer backbone through the chemical reaction mode, the method for preparing of the liquid embolizing agent that can self develop for a long time.
The technical scheme that the present invention solves the problems of the technologies described above employing is: a kind of method for preparing that contains the iodine liquid embolic agent capable of long-time self-developing; It is characterized in that: water miscible polyvinyl alcohol (PVA) reactant is added in the pyridine; Stir, evaporate and remove pyridine, residual reactant is dehumidified in dimethyl sulfoxide (DMSO) organic solvent, the dissolving back adds the solution that contains iodine compound and dichloromethane; Add triethylamine again; The iodine product (I-PVA) that contains of gained is poured into to precipitate in the mixture of butyl ether and acetone and is separated out, and after water washing, drying, reuse dimethyl sulfoxide or N-methyl-ketopyrrolidine organic solvent are configured to liquid embolizing agent.
Gained of the present invention contains in the iodine product (I-PVA) and contains the I that the covalent bonds X-ray can develop, and has long-term function of self developing.
Reactant polyvinyl alcohol according to the invention (PVA) degree of hydrolysis is 95%-98%, Mw=13-18KDa.
The iodine compound that contains according to the invention is that triiodo-benzene formyl chloride or N-(2.6-diiodo-carboxy phenyl)-3.4.5 triiodo-benzene formyl are pressed.It is said that to contain the percentage by weight of iodine product (I-PVA) in liquid embolizing agent be 30%-45%.Saidly contain that content of iodine is 35%-45% in the iodine product (I-PVA).
The liquid embolizing agent that adopts method of the present invention to prepare, it will contain iodine compound through the chemical reaction mode and be attached on the polymer backbone, make it have long-term development effect; Suppository is a liquid, and available microtubular is injected, and is easy to operate.In blood vessel, run into blood, organic solvent wherein is diffusion rapidly, thereby forms solid precipitation, plays the thromboembolism effect.Can be widely used in arteriovenous malformation of brain, external vessel pathological changes, and the embolotherapy of various tumors.The inventive method preparation is simple, and the iodine compound that contains of adding is attached on the polymer backbone through the chemical reaction mode, and stable performance can self be developed for a long time.This suppository has long-term developing function concurrently in vascular embolization, visible under x-ray fluoroscopy; When postoperative is followed up a case by regular visits to, need not to carry out again the angiography check, change but adopt simple CT surface sweeping can observe focus; Both reduced the patient suffering; Reduce medical expense, also reduced doctor's workload simultaneously, had good social benefit.
The specific embodiment
Below in conjunction with embodiment the present invention is done and to further describe.
The present invention contains the method for preparing of iodine liquid embolic agent capable of long-time self-developing; Water miscible polyvinyl alcohol (PVA) reactant is added in the pyridine; Stir, evaporate and remove pyridine, residual reactant is dehumidified in dimethyl sulfoxide (DMSO) organic solvent, the dissolving back adds the solution that contains iodine compound and dichloromethane; Add triethylamine again; The iodine product (I-PVA) that contains of gained is poured into to precipitate in the mixture of butyl ether and acetone and is separated out, and after water washing, drying, reuse dimethyl sulfoxide or N-methyl-ketopyrrolidine organic solvent are configured to liquid embolizing agent.
Gained of the present invention contains in the iodine product (I-PVA) and contains the I that the covalent bonds X-ray can develop, and has long-term function of self developing.
Reactant polyvinyl alcohol according to the invention (PVA) degree of hydrolysis is 95%-98%, Mw=13-18KDa.
The said iodine compound that contains is triiodo-benzene formyl chloride (or Triiodobenzoic acid) or N-(2.6-diiodo-carboxy phenyl)-3.4.5-triiodo-benzene Methanamide; Said organic solvent is dimethyl sulfoxide or N-methyl-ketopyrrolidine, and the said iodine product that contains is polyvinyl alcohol iodine (I-PVA).
According to the present invention, containing the percentage by weight of iodine product (I-PVA) in liquid embolizing agent is 30%-45%, is 35%-45% under the preferable case.Saidly contain that content of iodine is 35%-45% in the iodine product (I-PVA).
According to the present invention, it is the mixture with product and solvent mixture injection butyl ether and acetone that said deposition is separated out, and the product deposition is separated out.Butyl ether/acetone in the mixture of said butyl ether and acetone (volumetric ratio) is 80/20.Ratio is according to the present invention, the said water washing precipitate of using, and institute's water is a distilled water.According to the present invention, said drying is a vacuum drying.According to the present invention, said use organic solvent is configured to liquid embolizing agent for product (I-PVA) is dissolved in dimethyl sulfoxide (DMSO) or the N-methyl-ketopyrrolidine.
Embodiment 1
(1), at first synthesize and contain iodine product polyvinyl alcohol iodine (I-PVA): 6.0g puts into the 250ml round-bottomed flask with reactant polyvinyl alcohol (PVA) powder, adds the exsiccant pyridine of 30ml, stirs to make it to mix 2 hours; Then remove pyridine, surplus materials is dissolved in the exsiccant dimethyl sulfoxide of 100ml (DMSO), get rid of dampness with rotary evaporator; Slowly be warming up to 60 ℃; Use magnetic stirrer, all dissolve, be cooled to 45 ℃ then up to PVA; Drip the solution of 3.00g triiodo-benzene formyl chloride and 6ml dichloromethane, add excessive triithylamine (approximately 6ml) again.Mixture is cooled to room temperature; Continue to stir 24 hours, and poured the mixture in the flask in the butyl ether and acetone mixture of about 1g (mixture ratio is butyl ether/acetone=80/20) into collecting precipitation then; With water washing, vacuum drying, containing iodine product (I-PVA) is 4.5g.
(2), above-mentioned gained contained iodine product (I-PVA) 45g be dissolved in the exsiccant dimethyl sulfoxide of 55g (DMSO), fully mix, through sterilization, be and contain the iodine liquid embolic agent capable of long-time self-developing.
Embodiment 2
(1), at first synthesize and contain iodine product polyvinyl alcohol iodine (I-PVA): 6.0g puts into the 250ml round-bottomed flask with the PVA powder, adds the exsiccant pyridine of 30ml, stirs to make it to mix 2 hours; Then remove pyridine, surplus materials is dissolved in the exsiccant dimethyl sulfoxide of 100ml (DMSO), get rid of dampness with rotary evaporator; Slowly be warming up to 60 ℃; Use magnetic stirrer, all dissolve, be cooled to 45 ℃ then up to PVA; Drip 3.00gN-(2.6-diiodo-the carboxy phenyl)-chloride thing of 3.4.5-triiodo-benzene Methanamide and solution of 6ml dichloromethane, add excessive triithylamine (approximately 6ml) again.Mixture is cooled to room temperature; Continue to stir 24 hours, and poured the mixture in the flask in the butyl ether and acetone mixture of about 1g (mixture ratio is butyl ether/acetone=80/20) into collecting precipitation then; With water washing, vacuum drying, containing the Iod R product is 4.5g.
(2), above-mentioned gained contained iodine product (I-PVA) 40g be dissolved in 60gN-methyl-ketopyrrolidine, fully mix, through sterilization, be and contain the iodine liquid embolic agent capable of long-time self-developing.
Embodiment 3
Embodiment 1 gained is contained iodine product (I-PVA) 35g be dissolved in 65gN-methyl-ketopyrrolidine, fully mix, contain the iodine liquid embolic agent capable of long-time self-developing through sterilizing, being.
Embodiment 4
Embodiment 2 prepared iodine product (I-PVA) 30g that contain are dissolved among the exsiccant DMSD of 70g, fully mix, contain the iodine liquid embolic agent capable of long-time self-developing through sterilizing, being.
Claims (5)
1. method for preparing that contains the iodine liquid embolic agent capable of long-time self-developing; It is characterized in that: water miscible polyvinyl alcohol (PVA) reactant is added in the pyridine; Stir, evaporate and remove pyridine, residual reactant is dehumidified in dimethyl sulfoxide (DMSO) organic solvent, the dissolving back adds the solution that contains iodine compound and dichloromethane; Add triethylamine again; The iodine product polyvinyl alcohol iodine that contains of gained is poured into to precipitate in the mixture of butyl ether and acetone and is separated out, and after water washing, drying, reuse dimethyl sulfoxide or N-methyl-ketopyrrolidine organic solvent are configured to liquid embolizing agent; The said iodine compound that contains is triiodo-benzene formyl chloride or N-(2.6-diiodo-carboxy phenyl)-3.4.5-triiodo-benzene Methanamide.
2. the method for preparing that contains the iodine liquid embolic agent capable of long-time self-developing according to claim 1 is characterized in that: said polyvinyl alcohol (PVA) degree of hydrolysis is 95%-98%, Mw=13-18KDa.
3. the method for preparing that contains the iodine liquid embolic agent capable of long-time self-developing according to claim 1 is characterized in that: butyl ether in the mixture of said butyl ether and acetone/acetone volumetric ratio is 80/20.
4. the method for preparing that contains the iodine liquid embolic agent capable of long-time self-developing according to claim 1 is characterized in that: the percentage by weight of said polyvinyl alcohol iodine in liquid embolizing agent is 30%-45%.
5. the method for preparing of the liquid embolizing agent that can self develop for a long time according to claim 1, it is characterized in that: content of iodine is 35%-45% in the said polyvinyl alcohol iodine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9078950B2 (en) | 2012-10-15 | 2015-07-14 | Microvention, Inc. | Polymeric treatment compositions |
| US9351993B2 (en) | 2012-06-14 | 2016-05-31 | Microvention, Inc. | Polymeric treatment compositions |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2365009A1 (en) | 2010-03-10 | 2011-09-14 | Universite Claude Bernard Lyon 1 (UCBL) | Radiopaque, non-biodegradable, water-insoluble iodinated benzyl ethers of poly(vinyl alcohol), preparation method thereof, injectable embolizing compositions containing thereof and use thereof |
| US10368874B2 (en) | 2016-08-26 | 2019-08-06 | Microvention, Inc. | Embolic compositions |
| EP3694422A4 (en) | 2017-10-09 | 2021-06-30 | Microvention, Inc. | Radioactive liquid embolic |
| GB201810784D0 (en) * | 2018-06-29 | 2018-08-15 | Biocompatibles Uk Ltd | Radiopaque polymers |
| TW202031299A (en) * | 2018-11-13 | 2020-09-01 | 大陸商上海盛迪醫藥有限公司 | A polymer and compositons thereof |
| WO2021188685A1 (en) * | 2020-03-17 | 2021-09-23 | Microvention, Inc. | Liquid embolics |
| CN113651906B (en) * | 2020-05-12 | 2024-02-20 | 上海盛迪医药有限公司 | Copolymer and composition thereof |
| CN113995884A (en) * | 2021-09-10 | 2022-02-01 | 苏州浩微生物医疗科技有限公司 | Liquid embolic agent and preparation method thereof |
| CN115490639B (en) * | 2022-09-19 | 2023-05-16 | 科睿驰（深圳）医疗科技发展有限公司 | X-ray developing compound and preparation method thereof, and X-ray developing embolic material and preparation method thereof |
| CN117582535B (en) * | 2024-01-18 | 2024-04-26 | 上海汇禾医疗科技股份有限公司 | Liquid embolic agent and preparation method thereof |
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| WO1999012577A1 (en) * | 1997-09-05 | 1999-03-18 | Nycomed Imaging As | Polymer particles made of polyvinyl alcohol and comprising a contrast agent for chemoembolization |
| CN1569909A (en) * | 2004-05-11 | 2005-01-26 | 山东省医疗器械研究所 | Temperature-sensitive type polymer and liquid embolizing material , and preparation method thereof |
| CN1947803A (en) * | 2006-11-22 | 2007-04-18 | 山东赛克赛斯药业科技有限公司 | Non-viscous medical use liquid embolic agent |
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| WO1999012577A1 (en) * | 1997-09-05 | 1999-03-18 | Nycomed Imaging As | Polymer particles made of polyvinyl alcohol and comprising a contrast agent for chemoembolization |
| CN1569909A (en) * | 2004-05-11 | 2005-01-26 | 山东省医疗器械研究所 | Temperature-sensitive type polymer and liquid embolizing material , and preparation method thereof |
| CN1947803A (en) * | 2006-11-22 | 2007-04-18 | 山东赛克赛斯药业科技有限公司 | Non-viscous medical use liquid embolic agent |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9351993B2 (en) | 2012-06-14 | 2016-05-31 | Microvention, Inc. | Polymeric treatment compositions |
| US9937201B2 (en) | 2012-06-14 | 2018-04-10 | Microvention, Inc. | Polymeric treatment compositions |
| US10201562B2 (en) | 2012-06-14 | 2019-02-12 | Microvention, Inc. | Polymeric treatment compositions |
| US9078950B2 (en) | 2012-10-15 | 2015-07-14 | Microvention, Inc. | Polymeric treatment compositions |
| US9655989B2 (en) | 2012-10-15 | 2017-05-23 | Microvention, Inc. | Polymeric treatment compositions |
| US10258716B2 (en) | 2012-10-15 | 2019-04-16 | Microvention, Inc. | Polymeric treatment compositions |
| US11801326B2 (en) | 2012-10-15 | 2023-10-31 | Microvention, Inc. | Polymeric treatment compositions |
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