CN101125225A - Microsphere type embolic agent and preparation technology thereof - Google Patents
Microsphere type embolic agent and preparation technology thereof Download PDFInfo
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- CN101125225A CN101125225A CNA2007101432939A CN200710143293A CN101125225A CN 101125225 A CN101125225 A CN 101125225A CN A2007101432939 A CNA2007101432939 A CN A2007101432939A CN 200710143293 A CN200710143293 A CN 200710143293A CN 101125225 A CN101125225 A CN 101125225A
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Abstract
The invention provides a microsphere embolic agent, which is an elastic microsphere formed by the crosslink polymer of the functionalized macromolecules with the biocompatibility, and the particle size of the microsphere ranges from 1 Mum to 1500 Mum. The preparing technology includes the steps as follows: in a covalent link, linking a crosslinkable micromolecules with an acrylic acid structure on the polyvinyl alcohol, polyethylene glycol or polysaccharide macromolecules, forming the functionalized macromolecules; after that, the functionalized macromolecules and the monomer of the 2- acrylamide-2-methyl propanesulfonic acid undertakes opposite suspension polymerization, obtaining the crosslink polymeric microsphere embolic agent. The embolic agent has comparatively large retractility and elasticity, whose particle size is controllable and has perfect dispersiveness; moreover, the raw material is non-toxic and at the same time has good biocompatibility and stability. The preparing technology is a real chemosynthesis technology, whose material and preparing process does not produce any virus pollution, according with various requirements of the international embolic agent, which can replace various import and domestic expensive embolic agent products and is extensively applicable to various surgeries in the interventional radiology field.
Description
Technical field
The present invention relates to a kind of suppository and the preparation technology thereof of medical material tech field, be specifically related to a kind of microsphere type embolic agent and preparation technology thereof who is used for interventional therapy treatment tumor disease.
Background technology
Along with reaching its maturity of interventional therapy, it is just obtaining more and more widely application in field of medical technology.The principle of interventional therapy is the medical science shade instrument guiding by fine definition, through little otch conduit is inserted the intravital tumor locus of people, by the blood supply of feeding artery perfusion antitumor drug or blocking-up tumor tissues, make tumor interior downright bad, atrophy of short time more again, reach the purpose of treatment.The key technology of interventional therapy is to select suitable being used to block the embolism agent of granule of tumor tissues blood supply.The hybrid particles of paraffin and vaseline, osmanthus ball, cyanoacrylate, dehydrated alcohol, gelfoam, lyophilizing dura mater, granule of polyvinyl alcohol, iodized oil, stainless steel coil, viscose, thrombin and the fibrinous embolism agent of granule Ceng Xiangxu such as mixture that sticks occur and are applied to clinical, but these suppositories often are difficult to control, and can bring serious adverse.
In recent years, microsphere type embolic agent has obtained extensive use as a kind of novel particle suppository.Existing microsphere can be divided into polyvinyl alcohol microsphere, spherex, albumin microsphere, gelatine microsphere, polylactic acid microsphere, sodium alginate micro ball, chitosan microball and ethyl cellulose microsphere etc. by material therefor.Though the relatively unification of the shape of these microspheres, smooth surface, size are than homogeneous, and hydrophilic, suspension are better, be easy to blood flow guiding, but the total cross-section of occluding vascular and be difficult for recurrence, but the microsphere that wherein has does not have retractility and elasticity, very difficult distortion can return to original state again very soon by micro catheter smoothly, can cause incomplete thromboembolism, and the microsphere coefficient of expansion that has is excessive, when using, is difficult to select the microsphere size, and do not have the visuality of X line perspective, result of use is very undesirable.
Find through literature search prior art, the Chinese patent publication number is CN1872343, open day is the patent of invention of 2006.12.06, a kind of preparation technology of embolism agent of granule of polyvinyl alcohol is proposed, this technology is freezing by polyvinyl formal being added behind the sterile water for injection, cross sieve classification through digging broken processing and wet method again, obtain the polyvinyl formal wet granular, above-mentioned polyvinyl formal wet granular do not added the second time of injecting water freezing processing thereafter, form the polyvinyl formal granule, obtain the polyvinyl formal granule of all size size again through the dry screening classification.This preparation technology is comparatively simple, but the suppository size of preparation differs, and is difficult to separate, and above-mentioned suppository does not have biocompatibility simultaneously, and quality is hard, externally in vivo is difficult to identification and controls, and may cause incomplete thromboembolism.
Summary of the invention
The object of the present invention is to provide a kind of have good biocompatibility and stability, big elastic telescopic rate and recoverability, homogeneous grain diameter is controlled, and favorable dispersibility has targeting and can be used for the microsphere type embolic agent of various carcinoma cell therapies.
Another object of the present invention is to provide a kind of preparation technology of microsphere type embolic agent, its raw material sources extensively and to human body do not have any murder by poisoning side effect, and preparation technology is simple and direct, and is cheap for manufacturing cost, and the microsphere type embolic agent that makes has perfectly ball shape, and big or small homogeneous.
The present invention is achieved through the following technical solutions:
A kind of microsphere type embolic agent is characterized in that described suppository is the elastic microsphere that is polymerized by the functionalization macromolecules cross-linking with biocompatibility, microsphere particle size range 1～1500 μ m.
Particularly, be connected with on the macromolecular main chain of described functionalization and contain two at least and can make macromole be cross-linked to form the unsaturated functional groups of hydrogel through radical polymerization.
Described polymer is to have 1 on the main chain, 2-glycol or 1, the polymer of connection acetal structure functional group on the polyhydroxylated polymer of 3-diol structure functional group or the main chain.
Described polyhydroxylated polymer is polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular, and described polysaccharide macromolecular comprises amylose, chitosan or hydroxy methocel.
A kind of employing is prepared as follows the microsphere type embolic agent that technology obtains, and it is characterized in that the preparation technology of this microsphere embolization agent is as follows:
Polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular are dissolved in the water, add acrylates or esters, under 80～95 ℃ stirring condition, react, obtain the functionalization macromolecule hydrogel, the hydrogel that obtains is carried out vacuum drying;
In butyl acetate-water blending agent, add through exsiccant functionalization macromolecule hydrogel and 2-acrylamide-2-methyl propane sulfonic acid monomer, and the adding initiator carries out inverse suspension polymerization, the polymerization single polymerization monomer total concentration is 0.1～0.2g/L, wherein to account for total monomer quality be 70%～90% to the polyvinyl alcohol intermediate, and it is 2%～4% that 2-acrylamide-2-methyl propane sulfonic acid accounts for total monomer quality;
Polymeric reaction temperature is 50～70 ℃, and the response time is 6～8h, obtains this microsphere type embolic agent; Described polysaccharide macromolecular comprises amylose, chitosan or hydroxy methocel.
A kind of preparation technology of microsphere type embolic agent is characterized in that this preparation technology comprises the steps:
On polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular, connect a crosslinkable micromolecule with acrylic acid structure, form the functionalization macromolecule hydrogel with the form of covalent bond;
Functionalization macromolecule hydrogel and 2-acrylamide-2-methyl propane sulfonic acid monomer carries out inverse suspension polymerization, makes the microsphere type embolic agent of cross-linked polymeric.
A kind of preparation technology of microsphere type embolic agent is characterized in that this preparation technology is as follows:
Polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular are dissolved in the water, add acrylates or esters, under 80～95 ℃ stirring condition, react, obtain the functionalization macromolecule hydrogel, the hydrogel that obtains is carried out vacuum drying;
In butyl acetate-water blending agent, add through exsiccant hydrogel and 2-acrylamide-2-methyl propane sulfonic acid monomer, and the adding initiator carries out inverse suspension polymerization, the polymerization single polymerization monomer total concentration is 0.1～0.2g/L, wherein to account for total monomer quality be 70%～90% to functionalization macromole intermediate, and it is 2%～4% that 2-acrylamide-2-methyl propane sulfonic acid accounts for total monomer quality;
Polymeric reaction temperature is 50～70 ℃, and the response time is 6～8 hours, obtains this microsphere type embolic agent; Described polysaccharide macromolecular comprises amylose, chitosan or hydroxy methocel.
The preparation technology of above-mentioned microsphere type embolic agent, the molecular weight that it is characterized in that described polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular is 2 * 10
4～5 * 10
4, the mol ratio of polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular and acrylates or esters is 1: 6～1: 8;
Described initiator is persulfate, tetramethylethylenediamine or the two complex, and when selecting persulfate for use, adding concentration is 2 * 10
-3～4 * 10
-3G/L, when selecting tetramethylethylenediamine for use, adding concentration is 0.2 * 10
-2～2 * 10
-2G/L, described persulfate comprises Ammonium persulfate. or potassium peroxydisulfate.
Among the preparation technology of above-mentioned microsphere type embolic agent, described concrete preparation technology is as follows:
A) get molecular weight 2 * 10
4～5 * 10
4Polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular add in the entry, stir, it is fully dissolved after, add acrylates or esters under the room temperature, stirring reaction, product obtains gelatinous functionalization macromole intermediate behind washing, vacuum drying;
B) take by weighing 2-acrylamide-2-methyl propane sulfonic acid monomer and persulfate and be dissolved in the water, stir, it is fully dissolved, then add above-mentioned functions macromole intermediate, stir, obtain polymer monomer solution, other gets butyl acetate, adds cellulose acetate, feeds N simultaneously
2Gas, stir, in 50～70 ℃ of heated at constant temperature, add above-mentioned polymer monomer solution and tetramethylethylenediamine then successively, form oil-water hybrid reaction system, in this hybrid reaction system, the total concentration of polymer monomer is 0.1～0.2g/L, wherein functionalization macromole intermediate accounts for 70%～90% of total monomer quality, and 2-acrylamide-2-methyl propane sulfonic acid accounts for 2%～4% of total monomer quality, and persulfate concentration is 2 * 10
-3～4 * 10
-3G/L, tetramethylethylenediamine concentration is 0.2 * 10
-2～2 * 10
-2G/L, cellulose acetate concentration is 1 * 10
-2～2 * 10
-2G/L stirs this hybrid reaction system, and keeping temperature is 50～70 ℃, and making its reaction is 6～8h, after the reaction with this hybrid reaction system cooling, filter, filter thing behind butyl acetate, ethyl acetate washing, vacuum drying, obtain microsphere type embolic agent.
Described preparation technology also comprises staining procedure, and the microsphere type embolic agent that makes is put into water, adds reactive dye and dyes, and described reactive dye comprise reactive blue or reactive yellow.
Microsphere type embolic agent particle diameter of the present invention is than homogeneous, favorable dispersibility, outward appearance is perfectly ball, and can isolate the particle size range of a series of different sizes according to different demands, as 75～250 μ m, 250～500 μ m, 500～800 μ m and specification such as more than the 800 μ m, can be applicable to constitutional, metastatic liver, brain, bone, kidney, the treatment of carcinoma such as uterus is such as fibroma uteri thromboembolism, hepatoma carcinoma cell thromboembolism etc.This microsphere type embolic agent has good dilatation simultaneously, still can return to original state after can compressing 50%, so in operation process, can pass through micro catheter smoothly by distortion easily, can not stop up conduit, and after arriving target location, restore to the original state fast; This microsphere type embolic agent also has stronger targeting stationarity, can not cause occurring the mistake bolt because of producing anti-stream, reflux or flow to other organ; Fixed-site is stable, logical phenomenon can not occur again, need not to perform the operation once more.Simultaneously, this microsphere type embolic agent also can make it have color by dyeing, and vivo and vitro is identification easily all, is easy to control, and in addition, these microsphere type embolic agent physicochemical properties are stable, can never degenerate in depositing under the room temperature more than 2 years.
The present invention has adopted following method to prepare above-mentioned microsphere type embolic agent, at first, by at polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular, connect a crosslinkable micromolecule as the form with covalent bond on the macromole such as amylose, chitosan and hydroxy methocel with acrylic acid structure, make polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular functionalization, form gelatinous functionalization macromole intermediate.Moreover, adopt persulfate, tetramethylethylenediamine or both binary complexs as initiator, and by adding dispersant, in the oil-water hybrid reaction system that forms the microemulsion phase, cause functionalization macromole intermediate and 2-acrylamide-2-methyl propane sulfonic acid monomer and carry out inverse suspension polymerization, make microsphere with crosslinked swelling function, it is microsphere type embolic agent, in this course of reaction, 2-acrylamide-2-methyl propane sulfonic acid as one of monomer that participates in reaction, has also played the effect of dispersion stabilizer on the one hand on the other hand; In order to make above-mentioned microsphere type embolic agent easier controlling in the process that is applied to perform the operation, microsphere type embolic agent also can be by further dyeing processing, and used pigment can be selected dyestuffs such as reactive blue, reactive yellow for use, and its color can be adjusted according to the requirement of difference operation.
Show through human body and biotic experiment, this microsphere embolization agent be a kind of safe, effectively reach the novel embolizing agent of targeting, it is different from present medical treatment both at home and abroad and goes up the suppository that should not control in the operation commonly used, can arrive real tip, and can permanent relatively existence.This microsphere embolization agent adopts the polymeric biomaterial of water solublity, no side effects as raw material, and adopted the preparation technology of pure chemistry synthesis type, therefore can not cause and be similar to various infection diseases that the protein product that extracted by human body or animal and plant body causes as side effect such as AIDS, hepatitis, bovine spongiform encephalopathy, fowl plague, bird flu or albumen anaphylaxiss, and meet the requirement of suppository, the prescription of this microsphere embolization agent is highly stable in addition, can require to design accordingly according to the difference in the medical treatment.
Beneficial effect of the present invention is, this microsphere type embolic agent has big retractility and elasticity, and uniform particle diameter is controlled, favorable dispersibility, advantages of nontoxic raw materials, have good biocompatibility and stability simultaneously, and preparation technology is succinct, and is with low cost.This preparation technology adopts the pure chemistry synthesis technique, and can there be any viral pollution in its raw material and preparation process, meets every requirement of international suppository.This suppository can substitute the suppository goods of various imports and homemade costliness, for the patient provides the good carcinoma treatment of acceptable suppository, alleviate patient's sufferer misery and financial burden, and can be widely used in to obtain good therapeutic effect in the multiple operation in the interventional therapy field.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.
Embodiment 1
Take by weighing molecular weight 2 * 10
4-5 * 10
4Polyvinyl alcohol 100g, add in the 500g water, be heated to 90 ℃, simultaneously the speed with 190r/min stirs 2h, treat polyvinyl alcohol fully dissolve after with the solution cool to room temperature, add sodium acrylate 1.2g again, stir 6h with the speed of 190r/min, above-mentioned reactant fully reacted, after reaction is finished with the product vacuum drying, obtain gelatinous functionalization macromole intermediate, this intermediate can be preserved below room temperature.
Take by weighing 2-acrylamide-2-methyl propane sulfonic acid 1.63g, potassium peroxydisulfate 1.034g and water 17.3g mix, treat that potassium peroxydisulfate fully dissolves after, add above-mentioned functions macromole intermediate 40g, stir, obtain polymer monomer solution; Other gets butyl acetate 240mL, adds cellulose acetate 4.55g, fully stirs 10min, logical then N with the mixing speed of 240r/min
210min, heat this mixed solution simultaneously, make solution be warming up to 68 ℃, the adjustment mixing speed is 190r/min, when temperature rises to 65 ℃, slowly add above-mentioned polymer monomer solution, form the hybrid reaction system, after treating this hybrid reaction system reaction 10min, add tetramethylethylenediamine 0.78mL, react 6h again, above-mentioned hybrid reaction system natural cooling, filter, filter thing with butyl acetate, after ethyl acetate is repeatedly washed, through vacuum drying, obtain microsphere type embolic agent again, this suppository shape is near perfect spheroidal, smooth surface, particle size range is 1～1500 μ m, and compression deformation rate can reach more than 50%.Through external and zoopery, this microsphere type embolic agent has excellent biological compatibility and stability, can normally preserve more than 2 years in room temperature under the normal saline state.
Take by weighing the above-mentioned microsphere type embolic agent of 1kg, the washing 15min that blunges filters flushing, refilter, wash 15min again, refilter, then add 2kg water, stir, form the microsphere suspension, take by weighing the 0.2g reactive blue, add in this microsphere suspension, stir 20min under the room temperature, stirring is finished after-filtration and is cleaned three times, will filter to such an extent that thing is distributed in the water again after cleaning, and boils 15min once more, filter, obtain blue microsphere type embolic agent, microsphere embolization agent is stored in the normal saline.All discern easily with external in vivo through hyperchromatic microsphere type embolic agent, what enhancing was performed the operation can be handling.
Embodiment 2
Take by weighing molecular weight 3 * 10
4～4 * 10
4Macrogol 200 g, add in the 500g water, be heated to 80 ℃, simultaneously the speed with 100r/min stirs 2.5h, treat Polyethylene Glycol fully dissolve after with the solution cool to room temperature, add butyl acrylate 2.0g, stir 4h with the speed of 120r/min, it fully reacted, after reaction is finished with the product vacuum drying, obtain gelatinous functionalization macromole intermediate, this intermediate can be preserved below room temperature.
Take by weighing 2-acrylamide-2-methyl propane sulfonic acid 1.73g, potassium peroxydisulfate 1.044g and water 18.8g mix, treat that potassium peroxydisulfate fully dissolves after, add above-mentioned functions polyvinyl alcohol intermediate 45g, stir, obtain polymer monomer solution; Other gets butyl acetate 270mL, adds cellulose acetate 4.60g, fully stirs 10min, logical then N with the mixing speed of 300r/min
210min, heating simultaneously, make mixture be warming up to 68 ℃, the adjustment mixing speed is 240r/min, when temperature rises to 65 ℃, add above-mentioned polymer monomer solution, form the hybrid reaction system, treat its reaction 10min after, add tetramethylethylenediamine 0.78mL, react 7h again, with above-mentioned hybrid reaction system natural cooling, filtration, filter after thing repeatedly washs with butyl acetate, ethyl acetate, again through vacuum drying, obtain microsphere type embolic agent, the relatively unification of this suppository shape, smooth surface, particle diameter are 1～1500 μ m, and compression deformation rate is more than 50%.
Take by weighing the above-mentioned microsphere type embolic agent of 1kg, the washing 15min that blunges filters flushing, refilter, wash 15min again, refilter, then add 2kg water, stir, form the microsphere suspension, take by weighing the 0.2g reactive blue, add in this microsphere suspension, stir 20min under the room temperature, stirring is finished after-filtration and is cleaned three times, will filter to such an extent that thing is distributed in the water again after cleaning, and boils 15min once more, filter, obtain blue microsphere type embolic agent, preferably this microsphere embolization agent is stored in the normal saline.
Embodiment 3
Take by weighing molecular weight 4 * 10
4～5 * 10
4Amylose 100g, add in the 500g water, be heated to 90 ℃, simultaneously the speed with 190r/min stirs 3h, treat amylose fully dissolve after with the solution cool to room temperature, add sodium acrylate 1.2g, speed with 190r/min stirs 6h, and it is fully reacted, and reaction is finished the afterreaction product through vacuum drying, can obtain gelatinous functionalization macromole intermediate, this intermediate can be preserved below room temperature;
Take by weighing 2-acrylamide-2-methyl propane sulfonic acid 1.83g, potassium peroxydisulfate 1.054g and water 20.3g mix, treat that potassium peroxydisulfate fully dissolves after, add above-mentioned functions polyvinyl alcohol intermediate 40g, mix, obtain polymer monomer solution; Other gets butyl acetate 300mL, adds cellulose acetate 4.65g, fully stirs 10min, logical then N with the mixing speed of 360r/min
210min, heating simultaneously, make mixture be warming up to 68 ℃, the adjustment mixing speed is 290r/min, when temperature rises to 65 ℃, add above-mentioned polymer monomer solution, form the hybrid reaction system, treat its reaction 10min after, add tetramethylethylenediamine 0.78mL, react 8h again, with above-mentioned hybrid reaction system natural cooling, filtration, filter after thing repeatedly washs with butyl acetate, ethyl acetate, again through vacuum drying, obtain microsphere type embolic agent, the relatively unification of this suppository shape, smooth surface, particle diameter are 1～1500 μ m, and compression deformation rate is more than 50%.
Take by weighing the above-mentioned microsphere type embolic agent of 1kg, the washing 15min that blunges filters flushing, refilter, wash 15min again, refilter, then add 2kg water, stir, form the microsphere suspension, take by weighing the 0.2g reactive yellow, add in this microsphere suspension, stir 20min under the room temperature, stirring is finished after-filtration and is cleaned three times, will filter to such an extent that thing is distributed in the water again after cleaning, and boils 15min once more, filter, obtain xanchromatic microsphere type embolic agent, this microsphere embolization agent can be stored in the normal saline.
Embodiment 4
Take by weighing molecular weight 2 * 10
4～4 * 10
4Chitosan 150g, add in the 500g water, be heated to 95 ℃, simultaneously the speed with 190r/min stirs 2.8h, treat chitosan fully dissolve after with the solution cool to room temperature, add ethyl acrylate 1.5g, speed with 190r/min stirs 5.5h, and it is fully reacted, and reaction is finished the afterreaction product through vacuum drying, can obtain gelatinous functionalization macromole intermediate, this intermediate can be preserved below room temperature;
Take by weighing 2-acrylamide-2-methyl propane sulfonic acid 1.82g, potassium peroxydisulfate 1.055g and water 20.1g mix, treat that potassium peroxydisulfate fully dissolves after, add above-mentioned functions polyvinyl alcohol intermediate 40g, mix, obtain polymer monomer solution; Other gets butyl acetate 300mL, adds cellulose acetate 4.65g, fully stirs 10min, logical then N with the mixing speed of 360r/min
210min, heating simultaneously, make mixture be warming up to 68 ℃, the adjustment mixing speed is 290r/min, when temperature rises to 65 ℃, add above-mentioned polymer monomer solution, form the hybrid reaction system, treat its reaction 10min after, add tetramethylethylenediamine 0.78mL, react 8h again, with above-mentioned hybrid reaction system natural cooling, filtration, filter after thing repeatedly washs with butyl acetate, ethyl acetate, again through vacuum drying, obtain microsphere type embolic agent, the relatively unification of this suppository shape, smooth surface, particle diameter are 1～1500 μ m, and compression deformation rate is more than 50%.
Take by weighing the above-mentioned microsphere type embolic agent of 1kg, the washing 15min that blunges filters flushing, refilter, wash 15min again, refilter, then add 2kg water, stir, form the microsphere suspension, take by weighing the 0.2g reactive blue, add in this microsphere suspension, stir 20min under the room temperature, stirring is finished after-filtration and is cleaned three times, will filter to such an extent that thing is distributed in the water again after cleaning, and boils 15min once more, filter, obtain blue microsphere type embolic agent, this microsphere embolization agent can be stored in the normal saline.
Embodiment 5
Take by weighing molecular weight 3 * 10
4～4 * 10
4Hydroxy methocel 100g, add in the 500g water, be heated to 90 ℃, simultaneously the speed with 190r/min stirs 2.5h, treat hydroxy methocel fully dissolve after with the solution cool to room temperature, add acrylic acid methyl ester. 1.0g, speed with 190r/min stirs 6h, and it is fully reacted, and reaction is finished the afterreaction product through vacuum drying, can obtain gelatinous functionalization macromole intermediate, this intermediate can be preserved below room temperature;
Take by weighing 2-acrylamide-2-methyl propane sulfonic acid 1.80g, potassium peroxydisulfate 1.05g and water 20.0g mix, treat that potassium peroxydisulfate fully dissolves after, add above-mentioned functions polyvinyl alcohol intermediate 40g, mix, obtain polymer monomer solution; Other gets butyl acetate 300mL, adds cellulose acetate 4.65g, fully stirs 10min, logical then N with the mixing speed of 300r/min
210min, heating simultaneously, make mixture be warming up to 68 ℃, the adjustment mixing speed is 250r/min, when temperature rises to 65 ℃, add above-mentioned polymer monomer solution, form the hybrid reaction system, treat its reaction 10min after, add tetramethylethylenediamine 0.75mL, react 8h again, with above-mentioned hybrid reaction system natural cooling, filtration, filter after thing repeatedly washs with butyl acetate, ethyl acetate, again through vacuum drying, obtain microsphere type embolic agent, the relatively unification of this suppository shape, smooth surface, particle diameter are 1～1500 μ m, and compression deformation rate is more than 50%.
Take by weighing the above-mentioned microsphere type embolic agent of 1kg, the washing 15min that blunges filters flushing, refilter, wash 15min again, refilter, then add 2kg water, stir, form the microsphere suspension, take by weighing the 0.2g reactive blue, add in this microsphere suspension, stir 20min under the room temperature, stirring is finished after-filtration and is cleaned three times, will filter to such an extent that thing is distributed in the water again after cleaning, and boils 15min once more, filter, obtain blue microsphere type embolic agent, this microsphere embolization agent can be stored in the normal saline.
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. a microsphere type embolic agent is characterized in that described suppository is the elastic microsphere that is polymerized by the functionalization macromolecules cross-linking with biocompatibility, microsphere particle size range 1～1500 μ m.
2. microsphere type embolic agent according to claim 1 is characterized in that being connected with on the macromolecular main chain of described functionalization and contains two unsaturated functional groups that can make macromole be cross-linked to form hydrogel through radical polymerization at least.
3. microsphere type embolic agent according to claim 2 is characterized in that described functionalization macromole is to have 1 on the main chain, 2-glycol or 1, the polymer of connection acetal structure functional group on the polyhydroxylated polymer of 3-diol structure functional group or the main chain.
4. microsphere type embolic agent according to claim 3 is characterized in that described polyhydroxylated polymer can be polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular, and described polysaccharide macromolecular comprises amylose, chitosan or hydroxy methocel.
5. an employing is prepared as follows the microsphere type embolic agent that technology obtains, and it is characterized in that the preparation technology of this microsphere embolization agent is as follows:
Polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular are dissolved in the water, add acrylates or esters and under 80～95 ℃ stirring condition, react, obtain the functionalization macromolecule hydrogel, carry out vacuum drying obtaining the functionalization macromolecule hydrogel;
In butyl acetate-water blending agent, add through exsiccant function macromolecule hydrogel and 2-acrylamide-2-methyl propane sulfonic acid monomer, and the adding initiator carries out inverse suspension polymerization, the polymerization single polymerization monomer total concentration is 0.1～0.2g/L, wherein to account for total monomer quality be 70%～90% to the functionalization macromolecule hydrogel, and it is 2%～4% that 2-acrylamide-2-methyl propane sulfonic acid accounts for total monomer quality;
Polymeric reaction temperature is 50～70 ℃, and the response time is 6～8 hours, obtains this microsphere type embolic agent;
Described polysaccharide macromolecular comprises amylose, chitosan or hydroxy methocel.
6. the preparation technology of a microsphere type embolic agent is characterized in that this preparation technology comprises the steps:
On polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular, connect a crosslinkable micromolecule with acrylic acid structure, form the functionalization macromole with the form of covalent bond;
Functionalization macromole and 2-acrylamide-2-methyl propane sulfonic acid monomer carries out inverse suspension polymerization, makes the microsphere type embolic agent of cross-linked polymeric;
Described polysaccharide macromolecular comprises amylose, chitosan or hydroxy methocel.
7. the preparation technology of a microsphere type embolic agent is characterized in that this preparation technology is as follows:
Polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular are dissolved in the water, add acrylates or esters and under 80～95 ℃ stirring condition, react, obtain the functionalization macromolecule hydrogel, the functionalization macromolecule hydrogel that obtains is carried out vacuum drying;
In butyl acetate-water blending agent, add through exsiccant functionalization macromolecule hydrogel and 2-acrylamide-2-methyl propane sulfonic acid monomer, and the adding initiator carries out inverse suspension polymerization, the polymerization single polymerization monomer total concentration is 0.1～0.2g/L, wherein to account for total monomer quality be 70%～90% to the functionalization macromolecule hydrogel, and it is 2%～4% that 2-acrylamide-2-methyl propane sulfonic acid accounts for total monomer quality;
Polymeric reaction temperature is 50～70 ℃, and the response time is 6～8 hours, obtains microsphere type embolic agent;
Described polysaccharide macromolecular comprises amylose, chitosan or hydroxy methocel.
8. the preparation technology of microsphere type embolic agent according to claim 7, the molecular weight that it is characterized in that described polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular is 2 * 10
4～5 * 10
4, the mol ratio of polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular and acrylates or esters is 1: 6～1: 8;
Described initiator is persulfate, tetramethylethylenediamine or the two complex, and when selecting persulfate for use, adding concentration is 2 * 10
-3～4 * 10
-3G/L, when selecting tetramethylethylenediamine for use, adding concentration is 0.2 * 10
-2～2 * 10
-2G/L, described persulfate comprises Ammonium persulfate. or potassium peroxydisulfate, described polysaccharide macromolecular comprises amylose, chitosan or hydroxy methocel.
9. the preparation technology of microsphere type embolic agent according to claim 7 is characterized in that described concrete preparation technology is as follows:
A) get molecular weight 2 * 10
4～5 * 10
4Polyvinyl alcohol, Polyethylene Glycol or polysaccharide macromolecular add in the entry, stir, it is fully dissolved after, add acrylates or esters under the room temperature, stirring reaction, product obtains gelatinous functionalization macromole intermediate behind washing, vacuum drying;
B) take by weighing 2-acrylamide-2-methyl propane sulfonic acid monomer and persulfate and be dissolved in the water, stir, it is fully dissolved, then add above-mentioned functions macromole intermediate, stir, obtain polymer monomer solution, other gets butyl acetate, adds cellulose acetate, feeds N simultaneously
2Gas, stir, in 50～70 ℃ of heated at constant temperature, add above-mentioned polymer monomer solution and tetramethylethylenediamine then successively, form oil-water hybrid reaction system, in this hybrid reaction system, the total concentration of polymer monomer is 0.1～0.2g/L, wherein functionalization macromole intermediate accounts for 70%～90% of total monomer quality, and 2-acrylamide-2-methyl propane sulfonic acid accounts for 2%～4% of total monomer quality, and persulfate concentration is 2 * 10
-3～4 * 10
-3G/L, tetramethylethylenediamine concentration is 0.2 * 10
-2～2 * 10
-2G/L, cellulose acetate concentration is 1 * 10
-2～2 * 10
-2G/L stirs this hybrid reaction system, and keeping temperature is 50～70 ℃, and making its reaction is 6～8h, after the reaction with this hybrid reaction system cooling, filter, filter thing behind butyl acetate, ethyl acetate washing, vacuum drying, obtain microsphere type embolic agent.
10. according to the preparation technology of claim 6 or 7 described microsphere type embolic agents, it is characterized in that described preparation technology also comprises staining procedure, the microsphere type embolic agent that makes is put into water, add reactive dye and dye, described reactive dye comprise reactive blue or reactive yellow.
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