CN106729953A - A kind of functional modification Polyvinyl Alcohol Embolization microballoon and preparation method thereof - Google Patents
A kind of functional modification Polyvinyl Alcohol Embolization microballoon and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of functional modification Polyvinyl Alcohol Embolization microballoon and preparation method thereof, belong to medical science PCI field.It is base material that it uses polyvinyl alcohol, with acylation after crosslinkable amino/hydroxyl carboxylic acid derivates/sulfonic acid as modifying agent, after being modified be obtained.Modified microballoon obtained by present invention preparation is not only with the same perfect spherical form of polyvinyl alcohol microparticles before modified, single-size, good suspension and deformation elasticity.Simultaneously, due to introducing negatively charged many carboxyls or multi-sulfonic functional group, can be combined with positively charged small molecule, anti-tumor drug, so that microballoon has good drug carrying ability, non- functionalization can not carry the polyvinyl alcohol microparticles of medicine or only introduce the low microballoon of single negatively charged group drugloading rate in compared to existing technology, and the present invention has in terms of the gentle control releasability of drugloading rate and improves a lot.
Description
Technical field
The present invention relates to a kind of functional modification Polyvinyl Alcohol Embolization microballoon and preparation method thereof, belong to medical science PCI
Field.
Background technology
With the development of clinical treatment technology, percutaneous angiographic embolization is with its minimal invasive, whole image-guided and selection
Property target vessel insertion technology and accurate positioning the advantages of, be increasingly widely applied in interventional radiologic therapy field.
The principle of percutaneous angiographic embolization is, by high-resolution medical imaging device, will to be loaded with the artificial synthesized embolism of antineoplastic
Material injects blood vessel and makes angiemphraxis by conduit, so as to reach blocking blood vessel to tumor locus blood supply, and discharges antitumor
Medicine, makes Tumor shrank necrosis.The key of percutaneous angiographic embolization is the suitable band stype suppository of selection.
Current clinical practice is most widely microsphere type embolic agent.Existing microballoon can be divided into albumin microsphere according to matrix of materials
Ball, gelatine microsphere, spherex, polylactic acid microsphere, chitosan microball, sodium alginate micro ball, polyvinyl alcohol microparticles, ethyl cellulose
Plain microballoon etc..But these microballoons limit its Clinical practice due to respective many disadvantages, than if any microballoon shape it is irregular,
Size heterogeneity, so as to cause intervention to occur drift in performing the operation, block blood vessel, the by mistake side effect such as bolt, normal tissue causes to damage
Wound.Although some microballoon surfaces are smooth, shape is regular, size also than more uniform, and hydrophily and suspension are all fine, it is easy to
With blood flow be oriented to, but microballoon elasticity and retractility it is very poor, it is conductance bad, it is difficult to deform pass through micro catheter again can be quickly
Original state is returned to, so as to cause the incomplete embolism of blood vessel, and some microsphere expansion coefficients are excessive, it is micro- to be difficult selection in application
Ball size, and the visuality without X-ray examination, using effect are very undesirable, it is impossible to meet clinical PCI demand.This
Outward, it is clinical in recent years to favor in the use for carrying medicine embolism microball, in existing microballoon some can not combine chemotherapeutics or
Drugloading rate is low, limits the application of clinic.
Based on the defect of above unlike material microballoon, polymer microsphere with polyvinyl alcohol as representative with its surface it is smooth,
Size is homogeneous, perfectly round is spherical, good biocompatibility and suspension, in addition elasticity and retractility very well, gradually by
Extensive use and it is modified.Especially for the modified in the majority of medicine-carrying polymer microsphere, it is therefore an objective to increasing drugloading rate and carrying medicine
Being capable of slow release while speed.Literature search finds that studying more medicine-carrying polymer microsphere at present has polyvinylalcohol microsphere
Ball, gelatine microsphere and Ethylcellulose Microspheress etc..But gelatine microsphere, drugloading rate is low；The PVA microballoons of non-functional modification can not be carried
Medicine, and the PVA microballoon drugloading rates for only introducing single negatively charged group are low, sustained release amount is small.
In the patent of invention of Chinese invention patent Publication No. CN104857576, inventors herein propose a kind of synchronization and consolidate
The method that change prepares Polyvinyl Alcohol Embolization microballoon.The method is based on principle of hydrodynamics, in micro scale channel, with polyethylene
The fluid-mixing of alcohol solution, cross-linking agent aqueous solution and aqueous catalyst solution has as discrete phase fluid with water is immiscible
Machine solvent passes through the shearing force or extruding force and fluid boundary of continuous phase fluid as continuous phase fluid in two fluids intersection
Be divided into for discrete phase fluid the drop below the nanoliter level of discrete phase and nanoliter level, drop pass through by interaction between tension force
Synchronous cross-linking is cured as solid particle, and Polyvinyl Alcohol Embolization microballoon is obtained after scrubbed drying.Microsphere Size prepared by the method
It is homogeneous, controllable, good sphericity.But drug carrying ability is not referred to, the PCI use for needing drug bearing microsphere seems little.
The patent of invention of Chinese invention patent Publication No. CN104548123, proposes that a kind of acylation modification gelatin embolism is micro-
The preparation technology of ball.The technique carries out reaction modifying using acid anhydrides to gelatine microsphere, particular by the amino in gelatin with it is small
There is acylation reaction in molecule acid anhydrides, make the carboxyl containing higher density in modified gelatin.The preparation process of microballoon can be respectively
Take two methods：（1）First be modified balling-up again；（2）First balling-up reaction kinetic again.Purpose is prepared into containing ion-exchange group
The load medicine embolism microball of group.Microballoon form prepared by the technique is regular, and particle diameter is adjustable between 100~700uM, and is born in 24h
The carrying drug ratio of carrying anti-tumor drug adriamycin reaches as high as 35.9%, is greatly improved compared to pure gelatine microsphere carrying drug ratio 8.6%.But
Actual mechanical process is cumbersome, such as course of reaction need with absolute ethyl alcohol be demulsified, deionized water repeatedly washing by soaking remove unreacted
The process such as residue.
The content of the invention
It is an object of the present invention to overcome the above deficiencies, there is provided a kind of functional modification Polyvinyl Alcohol Embolization microballoon and
Its preparation method, it not only has the same perfect spherical form of polyvinyl alcohol microparticles before modified, single-size, good outstanding
Buoyancy and deformation elasticity, also with good drug carrying ability.
According to the technical scheme that the present invention is provided, a kind of functional modification Polyvinyl Alcohol Embolization microballoon, it uses polyethylene
Alcohol is base material, with acylation after crosslinkable amino/hydroxyl carboxylic acid derivates/sulfonic acid as modifying agent, after being modified
It is obtained.
Carboxylic acid derivates/the sulfonic acid of the amino/hydroxyl be in molecular formula containing one to two ten carbon atoms and
At least contain an amino/hydroxyl and two or more carboxyls/sulfonic many carboxyls or multi-sulfonic compound.
Carboxylic acid derivates/the sulfonic acid of the amino/hydroxyl is aspartic acid, aniline -2,5- disulfonic acids, 2- hydroxyls
In succinic acid, 2- naphthylamines -1,5- disulfonic acid, 5,6- diaminonaphthalene -1,3- disulfonic acid or the disulfonic acid of 2- amino -5- hydroxyl naphthalenes -1,7
One kind.
Carboxylic acid derivates/the sulfonic acid of the crosslinkable amino/hydroxyl is by alkyl alkene chloride derivative and ammonia
The crosslinkable compound containing unsaturated double-bond that the carboxylic acid derivates/sulfonic acid of base/hydroxyl is obtained through acylation reaction.
The alkyl alkene chloride derivative is the one kind in acryloyl chloride, crotonyl chloride or 4- prenyl chlorides.
The crosslinking agent is that acylation reaction occurs by aminoalkyl aldehyde dialkoxy acetal and alkyl alkene chloride derivative to obtain
To molecular formula at least contain two covalent bonds, while having the cross-linking small molecule of alkyl olefin(e) acid or derivatives thereof structure
Compound.
The aminoalkyl aldehyde dialkoxy acetal is that aminoacetaldehyde dimethyl acetal or aminoacetaldehyde diethyl second contract
Aldehyde.
The crosslinking agent is specially N acrylamide ethylhexanal dimethyl-acetal or N, N '-methylene-bisacrylamide base
Acetaldehyde dimethyl acetal.
The functionalized polyvinyl alcohol macromolecule hydrogel is have 1,2- glycol or 1,3- diol structure function on main chain
Roll into a ball and be connected with the polyhydroxylated polymer of crosslinking agent.
The preparation method of the functional modification Polyvinyl Alcohol Embolization microballoon, step is：
（1）The acylated synthesis of the carboxylic acid derivates/sulfonic acid of amino/hydroxyl：1~4 mol/L is added in four-hole boiling flask
200~400mL of sodium hydroxide solution, after ice salt bath is cooled to -5~15 DEG C, be added thereto to 20~50g amino/hydroxyl
Carboxylic acid derivates/sulfonic acid, start stirring, adjust 300~400 revs/min of speed of agitator；It is added dropwise over after stirring
Alkyl alkene chloride derivative, is added dropwise -5~15 DEG C of process control system temperature, the pH value of pH meter monitor in real time system, when pH value reaches
To stopping that alkyl alkene chloride derivative is added dropwise when 6.8~7.2, completion of dropping continues 10~30 points of stirring under the conditions of -5~15 DEG C
Clock, is then slowly increased to room temperature and continues to react 1~4 hour, and reaction uses hydrochloric acid regulation system pH value to 0.5~2.0 after terminating, so
Add 600~1200mL ethyl acetate to extract afterwards 2~6 times, collect concentrated by rotary evaporation after extract, obtain white after concentrate recrystallization
The powdered solid product of color, the carboxylic acid derivates/sulfonic acid of crosslinkable amino/hydroxyl after being as acylated；
（2）The synthesis of crosslinking agent：30~60g NaOH and 400~600mL purified waters are added in four-hole boiling flask, stirring makes
NaOH is completely dissolved, and ice salt bath is cooled to -5~15 DEG C, is added thereto to the contracting of 100~120g aminoalkyl aldehyde dialkoxy
Aldehyde, after stirring, is slowly added dropwise the alkyl alkene chloride derivative of equimolar amounts, control system temperature -5~15 during dropwise addition
DEG C, the pH value of pH meter monitor in real time system stops that alkyl alkene chloride derivative, insulation is added dropwise when pH value reaches 6.0~8.0
0.5~2 hour；100~300mL saturated nacl aqueous solutions agitator treating is added in reacted solution 0.5~2 hour, then
Extracted 1~4 time with 200~800mL methyl tertiary butyl ether(MTBE)s, it is small that extract 150~200g anhydrous sodium sulfate dryings are dehydrated 1~3
When after filter, filtrate carries out concentrated by rotary evaporation to evaporimeter condenser pipe dripless with Rotary Evaporators and oozes, concentrate adds 200 again~
1~4 removing impurity of 800mL petroleum ether extractions, the crude product that concentrated by rotary evaporation is obtained again after extraction is obtained through column chromatography purifying
Required crosslinking agent product；
（3）The synthesis of functionalized polyvinyl alcohol macromolecule hydrogel：To addition 1000~2000mL purified waters, side in there-necked flask
Stirring side adds 150~300g polyvinyl alcohol, and 90~100 DEG C are warming up to after adding stirring 10~30 minutes；Treat that polyvinyl alcohol is complete
Room temperature is cooled to after CL, 2.5~5.0g steps are added thereto to（2）The crosslinking agent of preparation, stirring is dripped after 10~30 minutes
Plus 100~200mL concentrated hydrochloric acids, 20~30 DEG C are warming up to after completion of dropping and continue to react 4~10 hours, reaction end is with concentration
The sodium hydroxide solution regulation system of 2.0~3.0mol/L to pH value is between 7.0~8.0, and to stablize 20~50 minutes.Then
Crude product is collected, through suction filtration removal of impurities, viscosity is concentrated into more than obtaining required function macromolecule hydrogel after 1500cps；
（4）The synthesis of modified polyvinylalcohol embolism microball：
A, 40~80g steps are sequentially added in beaker（1）Prepare the carboxylic acid derivates/sulphur of the amino/hydroxyl after gained is acylated
Acid derivative, 10~20g persulfates and 100~400g purified waters, the stirring and dissolving under the conditions of 15~30 DEG C treat persulfate
After being completely dissolved, 500~1000g steps are added（3）The functionalization macromolecule hydrogel of preparation, after stirring adjust viscosity to
300~500cps obtains the homogeneous liquid of polymer monomer, standby；
B, in four-hole boiling flask add 3000~6000mL butyl acetates as solvent, start stirring, adjust speed of agitator 200~
400 revs/min；50~100g acetylbutyrylcellulose homogeneous phase solutions are weighed as stabilizer, 20~40g purified waters are as dispersion
Phase；Nitrogen is passed through, system temperature adds step a to prepare the homogeneous liquid of resulting polymers monomer and 14~28mL after rising to 50~80 DEG C
Tetramethylethylenediamine, is consequently formed the inverse suspension polymerization reaction system of Water-In-Oil, and system continues to stir under the conditions of 50~80 DEG C
Mix reaction 3~6 hours；
In the reaction system, the total concentration of the homogeneous liquid of polymer monomer is 50~100g/L, wherein functionalization macromolecule hydrogel
The 60%~95% of total polymer monomer solution quality is accounted for, the carboxylic acid derivates/sulfonic acid of amino/hydroxyl accounts for total polymer list
The 4%~10% of liquid solution quality, persulfate concentration is 2~6 g/L, and tetramethylethylenediamine concentration is 1~5 g/L, and acetic acid is fine
The plain concentration of dimension is 2~8 g/L；
After c, reaction terminate, reaction dissolvent is filtered and microballoon is collected, then successively with 1000~3000mL butyl acetates, 1000
~3000mL ethyl acetate and 1000~3000mL acetone are washed, then by 50~60 DEG C of vacuum drying, obtain modified poly ethylene
Alcohol embolism microball crude product.
Modified polyvinylalcohol the present invention relates to be used for medical science PCI field（PVA）Embolism microball and its preparation work
Skill, is the Chinese invention patent [ZL 201010160644] to our company and the latest development of [ZL 201410232150].This
Polyvinyl Alcohol Embolization microballoon is carried out reaction modifying by invention, add in the building-up process of microballoon it is acylated after crosslinkable amino/
Alpha-hydroxy carboxylic acid derivatives or amino/hydroxyl sulfoacid derivative and introduce many carboxyls or multi-sulfonic functional group, be prepared into containing multiple
The function embolism microball of ion-exchange group.The microballoon not only has and the same regular shape of PVA microballoons before modified and
One size, particle diameter is between 50~1200uM and particle diameter is adjustable.Simultaneously as multiple ion-exchange groups are introduced, in theory
Microballoon has drugloading rate and more preferable slow release ability higher, solves like product drugloading rate on existing market low
Common fault, has good application prospect in tumor intervention therapeutic field.
Beneficial effects of the present invention：Modified microballoon obtained by present invention preparation not only has polyvinyl alcohol before modified
The same perfect spherical form of microballoon, single-size, good suspension and deformation elasticity.Simultaneously as introducing negatively charged
Many carboxyls of lotus or multi-sulfonic functional group, can be combined, so that microballoon with positively charged small molecule, anti-tumor drug
With good drug carrying ability, compared to existing technology in non-functionalization can not carry the polyvinyl alcohol microparticles of medicine or only introduce single band
The low microballoon of negative electrical charge group drugloading rate, the present invention has in terms of the gentle control releasability of drugloading rate and improves a lot.
Specific embodiment
The acylated synthesis of the carboxylic acid derivates/sulfonic acid of amino/hydroxyl
Embodiment 1
Add the sodium hydroxide solution 250mL of 2.5mol/L, after ice salt bath is cooled to 3.3 DEG C, add thereto in four-hole boiling flask
Enter 26.6g aspartic acids, start stirring, adjust 320 revs/min of speed of agitator.Acryloyl chloride is added dropwise over after stirring, is dripped
Plus 3.3 DEG C or so of process control system temperature, the pH value of pH meter monitor in real time system, stop being added dropwise third when pH value reaches 7.0
Alkene acyl chlorides, completion of dropping continues stirring 30 minutes under the conditions of 3.3 DEG C, is then slowly increased to room temperature and continues reaction 2.5 hours, instead
With hydrochloric acid regulation system pH value to 1.0 after should terminating, it is subsequently adding 800mL ethyl acetate and extracts 4 times, is rotated after collecting extract
Concentration, white powdery solids product is obtained after concentrate recrystallization, as acylated aspartic acid product, and weigh 43.7g.
Embodiment 2
Add the sodium hydroxide solution 300mL of 2.0mol/L, after ice salt bath is cooled to 7.8 DEG C, add thereto in four-hole boiling flask
Enter 2- hydroxysuccinic acid 26.8g, start stirring, adjust 400 revs/min of speed of agitator.Crotonoyl is added dropwise over after stirring
Chlorine, is added dropwise 7.8 DEG C or so of process control system temperature, and the pH value of pH meter monitor in real time system stops drop when pH value reaches 7.5
Plus crotonyl chloride, completion of dropping continue under the conditions of 7.8 DEG C stirring 20 minutes, be then slowly increased to room temperature continue react 1 hour,
Reaction uses hydrochloric acid regulation system pH value to 2.0 after terminating, be subsequently adding 600mL ethyl acetate and extract 2 times, is revolved after collecting extract
Inspissation is contracted, and white powdery solids product is obtained after concentrate recrystallization, and as acylated 2- hydroxysuccinic acid products are weighed
46.6g。
Embodiment 3
The sodium hydroxide solution 400mL of 1.0mol/L is added in four-hole boiling flask, after ice salt bath is cooled to 10 DEG C, is added thereto to
2- amino -5- hydroxyl naphthalene -1,7 disulfonic acid 64.0g start stirring, adjust 300 revs/min of speed of agitator.After stirring dropwise
Acryloyl chloride is added, 10 DEG C or so of process control system temperature, the pH value of pH meter monitor in real time system, when pH value reaches is added dropwise
Stop that acryloyl chloride is added dropwise when 7.8, completion of dropping continues stirring 30 minutes under the conditions of 10 DEG C, be then slowly increased to room temperature continuation
Reaction 2 hours, reaction uses hydrochloric acid regulation system pH value to 0.5 after terminating, be subsequently adding 1200mL ethyl acetate and extract 4 times, receives
Concentrated by rotary evaporation after collection extract, obtains white powdery solids product, as acylated 2- amino -5- hydroxyls after concentrate recrystallization
Base naphthalene -1,7 disulfonic acid products, weigh 140.4g.
The synthesis of crosslinking agent
Embodiment 4
48g NaOH and 480mL purified waters are added in four-hole boiling flask, stirring is completely dissolved NaOH, ice salt bath drop
Temperature is added thereto to 110g aminoacetaldehyde dimethyl acetals to 5.2 DEG C, after stirring, is slowly added dropwise the third of equimolar amounts
Alkene acyl chlorides, control system temperature is in 5 DEG C or so, the pH value of pH meter monitor in real time system, when pH value reaches 6.9 during dropwise addition
Stop that acryloyl chloride, insulation reaction 0.5 hour is added dropwise.Stirred to 160mL saturated nacl aqueous solutions are added in reacted solution
Washing 1 hour, then extracted 2 times with 500mL methyl tertiary butyl ether(MTBE)s, after extract is dehydrated 2 hours with 150g anhydrous sodium sulfate dryings
Filtering, filtrate carries out concentrated by rotary evaporation to evaporimeter condenser pipe dripless with Rotary Evaporators and oozes, and concentrate adds 300mL oil again
Ether extracts 3 removing impurity, and the crude product that concentrated by rotary evaporation is obtained again after extraction obtains required crosslinking agent and produces through column chromatography purifying
Product, weigh 82.2g.
Embodiment 5
30g NaOH and 400mL purified waters are added in four-hole boiling flask, stirring is completely dissolved NaOH, ice salt bath drop
Temperature is added thereto to 120g aminoacetaldehyde diethyl acetals to -5 DEG C, after stirring, is slowly added dropwise the propylene of equimolar amounts
Acyl chlorides, control system temperature is in -5 DEG C or so, the pH value of pH meter monitor in real time system, when pH value reaches 6.0 during dropwise addition
Stop that acryloyl chloride, insulation reaction 2 hours is added dropwise.Washed to the stirring of 300mL saturated nacl aqueous solutions is added in reacted solution
Wash 1.5 hours, then extracted 4 times with 800mL methyl tertiary butyl ether(MTBE)s, after extract is dehydrated 3 hours with 200g anhydrous sodium sulfate dryings
Filtering, filtrate carries out concentrated by rotary evaporation to evaporimeter condenser pipe dripless with Rotary Evaporators and oozes, and concentrate adds 600mL oil again
Ether extracts 4 removing impurity, and the crude product that concentrated by rotary evaporation is obtained again after extraction obtains required crosslinking agent and produces through column chromatography purifying
Product, weigh 103.6g.
Embodiment 6
60g NaOH and 600mL purified waters are added in four-hole boiling flask, stirring is completely dissolved NaOH, ice salt bath drop
Temperature is added thereto to 100g aminoacetaldehyde dimethyl acetals to 15 DEG C, after stirring, is slowly added dropwise the butylene of equimolar amounts
Acyl chlorides, control system temperature is in 15 DEG C or so, the pH value of pH meter monitor in real time system, when pH value reaches 8.0 during dropwise addition
Stop that crotonyl chloride, insulation reaction 2 hours is added dropwise.Washed to the stirring of 100mL saturated nacl aqueous solutions is added in reacted solution
Wash 2 hours, then with 200mL methyl tertiary butyl ether(MTBE)s extract 1 time, extract with 180g anhydrous sodium sulfate dryings be dehydrated 1 hour after mistake
Filter, filtrate carries out concentrated by rotary evaporation to evaporimeter condenser pipe dripless with Rotary Evaporators and oozes, and concentrate adds 200mL petroleum ethers again
1 removing impurity of extraction, the crude product that concentrated by rotary evaporation is obtained again after extraction obtains required crosslinking agent product through column chromatography purifying,
Weigh 77.8g.
The synthesis of functionalized polyvinyl alcohol macromolecule hydrogel
Embodiment 7
To 1500mL purified waters are added in there-necked flask, 180g polyvinyl alcohol is added while stirring, risen after adding stirring 20 minutes
Temperature is to 94 DEG C；Room temperature is cooled to after polyvinyl alcohol is completely dissolved, the crosslinking agent of the preparation of 2.75g embodiments 4 is added thereto to, stirred
125mL concentrated hydrochloric acids are added dropwise after mixing 15 minutes, 28 DEG C are warming up to after completion of dropping and continue to react 6.5 hours, reaction terminate after with dense
Spend for sodium hydroxide solution regulation system to the pH value of 2.0mol/L is 7.2, and stablize 40 minutes.Then crude product is collected, is passed through
Required function macromolecule hydrogel is obtained after suction filtration removal of impurities, concentration, viscosity is 1974cps.
Embodiment 8
To 1000mL purified waters are added in there-necked flask, 150g polyvinyl alcohol is added while stirring, risen after adding stirring 15 minutes
Temperature is to 90 DEG C；Room temperature is cooled to after polyvinyl alcohol is completely dissolved, the crosslinking agent of the preparation of 3.05g embodiments 5 is added thereto to, stirred
100mL concentrated hydrochloric acids are added dropwise after mixing 20 minutes, 30 DEG C are warming up to after completion of dropping and continue to react 6.0 hours, reaction terminate after with dense
Spend for sodium hydroxide solution regulation system to the pH value of 2.5mol/L is 7.0, and stablize 30 minutes.Then crude product is collected, is passed through
Required function macromolecule hydrogel is obtained after suction filtration removal of impurities, concentration, viscosity is 1880cps.
Embodiment 9
To 2000mL purified waters are added in there-necked flask, 300g polyvinyl alcohol is added while stirring, risen after adding stirring 30 minutes
Temperature is to 100 DEG C；Room temperature is cooled to after polyvinyl alcohol is completely dissolved, the crosslinking agent of the preparation of 4.98g embodiments 6 is added thereto to,
Stirring is added dropwise 200mL concentrated hydrochloric acids after 30 minutes, 25 DEG C is warming up to after completion of dropping and continues to react 10 hours, reaction terminate after with dense
Spend for sodium hydroxide solution regulation system to the pH value of 3.0mol/L is 7.5, and stablize 30 minutes.Then crude product is collected, is passed through
Required function macromolecule hydrogel is obtained after suction filtration removal of impurities, concentration, viscosity is 2016cps.
The synthesis of modified polyvinylalcohol embolism microball
Embodiment 10
A, sequentially add in beaker 42.760g embodiments 1 prepare gained it is acylated after aspartic acid, 12.125g potassium peroxydisulfates
With 198g purified waters, the stirring and dissolving under the conditions of 25 DEG C, after treating that potassium peroxydisulfate is completely dissolved, prepared by addition 510g embodiments 7
Functionalization macromolecule hydrogel, viscosity is adjusted after stirring and obtains the homogeneous liquid of polymer monomer to 368cps, it is standby；
B, in four-hole boiling flask add 3500mL butyl acetates as solvent, start stirring, 330 revs/min of speed of agitator of regulation.
54.801g acetylbutyrylcelluloses homogeneous phase solution is weighed as stabilizer, 26.664g purified waters are as dispersed phase；It is passed through nitrogen,
System temperature rises to 66 DEG C and adds step a to prepare the homogeneous liquid of resulting polymers monomer and 15.6mL tetramethylethylenediamines afterwards, by
This forms the inverse suspension polymerization reaction system of Water-In-Oil, and system continues stirring reaction 4 hours under the conditions of 60 DEG C;
After c, reaction terminate, reaction dissolvent is filtered and microballoon is collected, 1000mL butyl acetates, 1000mL acetic acid are then used successively
Ethyl ester and 1000mL acetone are washed, then by 56 DEG C of vacuum drying, obtain modified polyvinylalcohol embolism microball crude product.
Embodiment 11
A, sequentially add in beaker 45.882g embodiments 2 prepare gained it is acylated after 2- hydroxysuccinic acids, 18.918g over cures
Sour potassium and 202g purified waters, the stirring and dissolving under the conditions of 25 DEG C after treating that potassium peroxydisulfate is completely dissolved, add 660g embodiments 8
The functionalization macromolecule hydrogel of preparation, adjusts viscosity and obtains the homogeneous liquid of polymer monomer to 320cps after stirring, standby；
B, in four-hole boiling flask add 4500mL butyl acetates as solvent, start stirring, 200 revs/min of speed of agitator of regulation.
82.636g acetylbutyrylcelluloses homogeneous phase solution is weighed as stabilizer, 28.219g purified waters are as dispersed phase；It is passed through nitrogen,
System temperature rises to 50 DEG C and adds step a to prepare the homogeneous liquid of resulting polymers monomer and 20.2mL tetramethylethylenediamines afterwards, by
This forms the inverse suspension polymerization reaction system of Water-In-Oil, and system continues stirring reaction 6 hours under the conditions of 50 DEG C;
After c, reaction terminate, reaction dissolvent is filtered and microballoon is collected, 2000mL butyl acetates, 2000mL acetic acid are then used successively
Ethyl ester and 2000mL acetone are washed, then by 50 DEG C of vacuum drying, obtain modified polyvinylalcohol embolism microball crude product.
Embodiment 12
A, sequentially add in beaker 77.2g embodiments 3 prepare gained it is acylated after 2- amino -5- hydroxyl naphthalene -1,7 disulfonic acid,
10.269g potassium peroxydisulfates and 400g purified waters, the stirring and dissolving under the conditions of 25 DEG C after treating that potassium peroxydisulfate is completely dissolved, are added
Functionalization macromolecule hydrogel prepared by 1000g embodiments 9, adjusts viscosity and obtains polymer monomer to 304cps after stirring
Homogeneous liquid, it is standby；
B, in four-hole boiling flask add 6000mL butyl acetates as solvent, start stirring, 400 revs/min of speed of agitator of regulation.
98.991g acetylbutyrylcelluloses homogeneous phase solution is weighed as stabilizer, 39.687g purified waters are as dispersed phase；It is passed through nitrogen,
System temperature rises to 80 DEG C and adds step a to prepare the homogeneous liquid of resulting polymers monomer and 20.2mL tetramethylethylenediamines afterwards, by
This forms the inverse suspension polymerization reaction system of Water-In-Oil, and system continues stirring reaction 3 hours under the conditions of 80 DEG C;
After c, reaction terminate, reaction dissolvent is filtered and microballoon is collected, 3000mL butyl acetates, 3000mL acetic acid are then used successively
Ethyl ester and 3000mL acetone are washed, then by 60 DEG C of vacuum drying, obtain modified polyvinylalcohol embolism microball crude product.
The present invention compared with product ratio, 1）Carboxylic acid derivates/sulfonic acid with acylated amino/hydroxyl is to change
Property agent, functional modification is carried out to Polyvinyl Alcohol Embolization microballoon.Carboxylic acid derivates/the sulfonic acid of amino/hydroxyl is molecule
In formula containing one to two ten carbon atoms and at least containing amino/hydroxyl and two or more carboxyls/it is sulfonic many
Carboxyl or multi-sulfonic compound.Carboxylic acid derivates/the sulfonic acid of crosslinkable amino/hydroxyl is by alkyl alkene after acylation
Chloride derivative（Such as acryloyl chloride, crotonyl chloride, first-selected acryloyl chloride）With amino/alpha-hydroxy carboxylic acid derivatives or amino/hydroxyl
The crosslinkable compound containing unsaturated double-bond that base sulfonic acid is obtained through acylation reaction.Alkyl alkene chloride derivative is included
Carbon number three to two ten. 2）Introduced by adding many carboxyls or multi-sulfonic compound in the building-up process of microballoon
Multiple negatively charged functional groups increase the drugloading rate of microballoon.
Claims (11)
1. a kind of functional modification Polyvinyl Alcohol Embolization microballoon, it is characterized in that：It is base material that it uses polyvinyl alcohol, with can after acylation
Carboxylic acid derivates/the sulfonic acid of the amino/hydroxyl of crosslinking is modifying agent, is obtained after being modified.
2. functional modification Polyvinyl Alcohol Embolization microballoon as claimed in claim 1, it is characterized in that：The carboxylic acid of the amino/hydroxyl
Derivative/sulfonic acid be molecular formula in containing one to two ten carbon atoms and at least contain an amino/hydroxyl and two
Or two or more carboxyl/sulfonic many carboxyls or multi-sulfonic compound.
3. functional modification Polyvinyl Alcohol Embolization microballoon as claimed in claim 2, it is characterized in that：The carboxylic acid of the amino/hydroxyl
Derivative/sulfonic acid be aspartic acid, aniline -2,5- disulfonic acids, 2- hydroxysuccinic acids, 2- naphthylamines -1,5- disulfonic acid, 5,
One kind in 6- diaminonaphthalene -1,3- disulfonic acid or the disulfonic acid of 2- amino -5- hydroxyl naphthalenes -1,7.
4. functional modification Polyvinyl Alcohol Embolization microballoon as claimed in claim 1, it is characterized in that：Crosslinkable amino/the hydroxyl
Carboxylic acid derivates/the sulfonic acid of base is derived by the carboxylic acid derivates/sulfonic acid of alkyl alkene chloride derivative and amino/hydroxyl
The crosslinkable compound containing unsaturated double-bond that thing is obtained through acylation reaction.
5. functional modification Polyvinyl Alcohol Embolization microballoon as claimed in claim 4, it is characterized in that：The alkyl alkene chloride derivative
It is the one kind in acryloyl chloride, crotonyl chloride or 4- prenyl chlorides.
6. functional modification Polyvinyl Alcohol Embolization microballoon as claimed in claim 1, it is characterized in that：The crosslinking agent is by amino alkane
Base aldehyde dialkoxy acetal occurs at least to contain two covalently in the molecular formula that acylation reaction is obtained with alkyl alkene chloride derivative
Key, while having the cross-linking micromolecular compound of alkyl olefin(e) acid or derivatives thereof structure.
7. functional modification Polyvinyl Alcohol Embolization microballoon as claimed in claim 6, it is characterized in that：The aminoalkyl aldehyde dialkoxy
Base acetal is aminoacetaldehyde dimethyl acetal or aminoacetaldehyde diethyl acetal.
8. functional modification Polyvinyl Alcohol Embolization microballoon as claimed in claim 6, it is characterized in that：The crosslinking agent is specially N- third
Acrylamide ethylhexanal dimethyl-acetal or N, N '-methylene-bisacrylamide ethylhexanal dimethyl-acetal.
9. functional modification Polyvinyl Alcohol Embolization microballoon as claimed in claim 1, it is characterized in that：The functionalized polyvinyl alcohol is big
Molecule hydrogel is on main chain have 1,2- glycol or 1,3- diol structure functional group and be connected with the polyhydroxylated polymer of crosslinking agent.
10. the preparation method of functional modification Polyvinyl Alcohol Embolization microballoon described in claim 1, it is characterized in that step is：
（1）The acylated synthesis of the carboxylic acid derivates/sulfonic acid of amino/hydroxyl：1~4 mol/L is added in four-hole boiling flask
200~400mL of sodium hydroxide solution, after ice salt bath is cooled to -5~15 DEG C, be added thereto to 20~50g amino/hydroxyl
Carboxylic acid derivates/sulfonic acid, start stirring, adjust 300~400 revs/min of speed of agitator；It is added dropwise over after stirring
Alkyl alkene chloride derivative, is added dropwise -5~15 DEG C of process control system temperature, the pH value of pH meter monitor in real time system, when pH value reaches
To stopping that alkyl alkene chloride derivative is added dropwise when 6.8~7.2, completion of dropping continues 10~30 points of stirring under the conditions of -5~15 DEG C
Clock, is then slowly increased to room temperature and continues to react 1~4 hour, and reaction uses hydrochloric acid regulation system pH value to 0.5~2.0 after terminating, so
Add 600~1200mL ethyl acetate to extract afterwards 2~6 times, collect concentrated by rotary evaporation after extract, obtain white after concentrate recrystallization
The powdered solid product of color, the carboxylic acid derivates/sulfonic acid of crosslinkable amino/hydroxyl after being as acylated；
（2）The synthesis of crosslinking agent：30~60g NaOH and 400~600mL purified waters are added in four-hole boiling flask, stirring makes
NaOH is completely dissolved, and ice salt bath is cooled to -5~15 DEG C, is added thereto to the contracting of 100~120g aminoalkyl aldehyde dialkoxy
Aldehyde, after stirring, is slowly added dropwise the alkyl alkene chloride derivative of equimolar amounts, control system temperature -5~15 during dropwise addition
DEG C, the pH value of pH meter monitor in real time system stops that alkyl alkene chloride derivative, insulation is added dropwise when pH value reaches 6.0~8.0
0.5~2 hour；100~300mL saturated nacl aqueous solutions agitator treating is added in reacted solution 0.5~2 hour, then
Extracted 1~4 time with 200~800mL methyl tertiary butyl ether(MTBE)s, it is small that extract 150~200g anhydrous sodium sulfate dryings are dehydrated 1~3
When after filter, filtrate carries out concentrated by rotary evaporation to evaporimeter condenser pipe dripless with Rotary Evaporators and oozes, concentrate adds 200 again~
1~4 removing impurity of 800mL petroleum ether extractions, the crude product that concentrated by rotary evaporation is obtained again after extraction is obtained through column chromatography purifying
Required crosslinking agent product；
（3）The synthesis of functionalized polyvinyl alcohol macromolecule hydrogel：To addition 1000~2000mL purified waters, side in there-necked flask
Stirring side adds 150~300g polyvinyl alcohol, and 90~100 DEG C are warming up to after adding stirring 10~30 minutes；Treat that polyvinyl alcohol is complete
Room temperature is cooled to after CL, 2.5~5.0g steps are added thereto to（2）The crosslinking agent of preparation, stirring is dripped after 10~30 minutes
Plus 100~200mL concentrated hydrochloric acids, 20~30 DEG C are warming up to after completion of dropping and continue to react 4~10 hours, reaction end is with concentration
The sodium hydroxide solution regulation system of 2.0~3.0mol/L to pH value is between 7.0~8.0, and to stablize 20~50 minutes.
11. and then crude product is collected, through suction filtration removal of impurities, be concentrated into viscosity more than obtaining required function macromolecular after 1500cps
Hydrogel；
（4）The synthesis of modified polyvinylalcohol embolism microball：
A, 40~80g steps are sequentially added in beaker（1）Prepare the carboxylic acid derivates/sulphur of the amino/hydroxyl after gained is acylated
Acid derivative, 10~20g persulfates and 100~400g purified waters, the stirring and dissolving under the conditions of 15~30 DEG C treat persulfate
After being completely dissolved, 500~1000g steps are added（3）The functionalization macromolecule hydrogel of preparation, after stirring adjust viscosity to
300~500cps obtains the homogeneous liquid of polymer monomer, standby；
B, in four-hole boiling flask add 3000~6000mL butyl acetates as solvent, start stirring, adjust speed of agitator 200~
400 revs/min；50~100g acetylbutyrylcellulose homogeneous phase solutions are weighed as stabilizer, 20~40g purified waters are as dispersion
Phase；Nitrogen is passed through, system temperature adds step a to prepare the homogeneous liquid of resulting polymers monomer and 14~28mL after rising to 50~80 DEG C
Tetramethylethylenediamine, is consequently formed the inverse suspension polymerization reaction system of Water-In-Oil, and system continues to stir under the conditions of 50~80 DEG C
Mix reaction 3~6 hours；
After c, reaction terminate, reaction dissolvent is filtered and microballoon is collected, then successively with 1000~3000mL butyl acetates, 1000
~3000mL ethyl acetate and 1000~3000mL acetone are washed, then by 50~60 DEG C of vacuum drying, obtain modified poly ethylene
Alcohol embolism microball crude product.
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