CN103550832B - A kind of embolism materials and its production and use - Google Patents
A kind of embolism materials and its production and use Download PDFInfo
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- CN103550832B CN103550832B CN201310513259.1A CN201310513259A CN103550832B CN 103550832 B CN103550832 B CN 103550832B CN 201310513259 A CN201310513259 A CN 201310513259A CN 103550832 B CN103550832 B CN 103550832B
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- embolism materials
- materials according
- embolism
- acrylamide
- acid
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Landscapes
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Abstract
The invention provides a kind of embolism materials and its production and use, this embolism materials is generated by polyreaction by reactant feed, described reactant feed comprises: nuclear magnetic resonance material, and contain the monomer of unsaturated double-bond and anionic group, wherein, in the polymer that described reactant feed is generated by polyreaction, on the anionic group that described nuclear magnetic resonance material is bonded to the polymer of generation or dispersion in the polymer.Embolism materials of the present invention enable doctor in Embolization and postoperative check time to be monitored by MRI and to locate this embolism materials, be conducive to the efficacy and saferry of raising embolotherapy.
Description
Technical field
The invention belongs to interventional medical arts, relate to a kind of embolism materials and its production and use.
Background technology
Interventional therapy is 21st century development one of subject the most rapidly.Run neck and neck with medical treatment and surgical intervention at present, become the third therapy system.
Embolotherapy is the important component part of interventional therapy, belongs to invasive treatment.Embolotherapy is under the guiding of medical imaging device, and suppository is introduced human body by the special precision instruments such as seal wire, conduit, artificially occluding vascular and the topical therapeutic that carries out.Embolization therapy all has good curative effect in treatment hysteromyoma, hepatocarcinoma, renal carcinoma, hemangioma, vascular malformation and hemostasis etc., has become the alternative medicine of partial surgical treatment.
Embolism materials conventional clinically at present mainly contains polyvinyl alcohol irregular particle type or microsphere type embolic agent, gelfoam irregular particle type or microsphere type embolic agent etc.These embolism materials all can not be directly detected by existing Clinical detection means, comprise X ray image equipment (digital outline contrast machine (Digital Subtraction Angiography, and computed tomography (ComputedTomography DSA),) and nuclear magnetic resonance (Magnetic Resonance Imaging, MRI) CT).In practical application, can only the flowing of contrast agent be checked by DSA and indirectly infer position and the thromboembolism terminal at suppository place.A nearest clinical research shows, judges that uterine artery is by the case of complete thromboembolism, has 20% not reach complete thromboembolism by this method, and postoperative MRI checks that the part uterine artery of these patients of display still has blood to supply.Therefore, this indirect determination methods can not judge position and the thromboembolism terminal at suppository place in time, exactly, have impact on the efficacy and saferry of embolotherapy.So, how to enable embolism materials directly be detected by existing Clinical detection means with during postoperative check in Embolization, become this area problem urgently to be resolved hurrily with the efficacy and saferry improving embolotherapy.
Summary of the invention
For the problems referred to above, one object of the present invention is to provide a kind of embolism materials, enable doctor in Embolization and postoperative check time to be monitored by MRI and to locate this embolism materials, be conducive to the efficacy and saferry of raising embolotherapy.
Another object of the present invention is to the preparation method that a kind of above-mentioned embolism materials is provided.
Another object of the present invention is to provide above-mentioned embolism materials for the preparation for the treatment of tumor, such as hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma or malignant breast tumor, or vascular malformation or for the purposes in the medicine that stops blooding.
For achieving the above object, the invention provides a kind of embolism materials, it is generated by polyreaction by reactant feed, and described reactant feed comprises:
Nuclear magnetic resonance material, and
Monomer containing unsaturated double-bond and anionic group,
Wherein, described reactant feed generates polymer by polyreaction, on the anionic group that described nuclear magnetic resonance material is bonded to described polymer or dispersion in the polymer.
Further, described reactant feed comprises:
On the anionic group that wherein said medicine is bonded to described polymer or dispersion in the polymer, described nuclear magnetic resonance material is calculated with the gauge of magnetic metal element.
Further, described reactant feed comprises:
Preferably, described embolism materials is prepared by making polymer particles, magnetic metal ion and alkali substance reaction, and described raw material comprises the nuclear magnetic resonance material of 0.07-20 weight portion, preferably 0.5-15 weight portion;
Preferably, described embolism materials is prepared by magnetic particle and the monomer containing unsaturated double-bond and anionic group, and described raw material comprises the nuclear magnetic resonance material of 0.001-1 weight portion, preferably 0.007-0.5 weight portion;
Preferably, described embolism materials comprises medicine further, and the drug loading of described embolism materials is 0-120.3mg/ml, preferred 10.2-100.1mg/ml.
Further, described nuclear magnetic resonance material is oxide or the magnetic metal ion of magnetic metal element; Preferably, the oxide of described magnetic metal element is selected from Fe
3o
4, Fe
2o
3, MnFe
2o
4, CoFe
2o
4, NiFe
2o
4or one or more in the oxide of holmium, gadolinium, europium, terbium, dysprosium, thulium, ytterbium etc.; Preferably, one or more in described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium plasma, preferably two or three, be more preferably the mixture of ferric ion and ferrous ion;
Preferably, the described monomer containing unsaturated double-bond and anionic group is selected from one or more in acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid, 2-acrylamide-2-methylpro panesulfonic acid salt, sodium allylsulfonate, methacrylic acid or methacrylate etc.; Preferred acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid or 2-acrylamide-2-methylpro panesulfonic acid salt; More preferably the mixture be made up of acrylic acid and acrylates, the mixture be made up of acrylic acid and 2-acrylamide-2-methylpro panesulfonic acid, the mixture be made up of 2-acrylamide-2-methylpro panesulfonic acid and 2-acrylamide-2-methylpro panesulfonic acid salt or the mixture be made up of acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid and 2-acrylamide-2-methylpro panesulfonic acid salt; The preferred sodium acrylate of wherein said acrylates, described 2-acrylamide-2-methylpro panesulfonic acid salt preferred 2-acrylamide-2-methylpro panesulfonic acid sodium; Preferably, described anionic group is selected from one or more in carboxylate anion, azochlorosulfonate acid anion, sulfate anion, phosphonate radical anion, nitrate anion, carbonate anion or phosphate radical anion etc.; Be preferably carboxylate anion or azochlorosulfonate acid anion.
Further, the described macromolecular material containing hydroxyl be selected from polyvinyl alcohol, alginic acid, chitosan, cellulose or amylose etc. one or more, be preferably polyvinyl alcohol;
Preferably, described vinyl monomer be selected from acrylamide, acrylonitrile, acrylate or methacrylate etc. one or more, preferred acrylamide or methacrylic acid-2-hydroxy methacrylate;
Preferably, described medicine is selected from one or more in antitumor drug, local anaesthesia medicine, antipyretic-antalgic anti-inflammatory agent thing or antibiotic medicine etc.;
Preferably, described antitumor drug is selected from one or more in amycin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel, Docetaxel, 5-fluorouracil, Bleomycin A5, Sutent (Sunitinib), Sorafenib (Sorafenib), gefitinib (Gefitinib), imatinib (Imatinib), PTK787 (Vatalanib) or its salt etc.;
Preferably, described local anaesthesia medicine is selected from one or more in procaine, chloroprocaine, hydroxyprocaine, tetracaine, parethoxycaine, empty Tuo Kayin, dimethocaine, lignocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, supernatural power caine, quinisocaine, phenacaine or its salt etc.;
Preferably, described antipyretic-antalgic anti-inflammatory agent thing is selected from one or more in aspirin, magnesium salicylate, sodium salicylate, choline magnesium trisalicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, fenoprofen, naproxen, nabumetone, piroxicam, Phenylbutazone, acetaminophen, diclofenac, venlofen, ketone ibuprofen, ketorolac, four clofenamic acides, sulindac or tolmetin etc.;
Preferably, described antibiotic medicine is selected from beta-lactam antibiotic (such as penicillin, oxacillin sodium, ampicillin, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid or sulbactam), tetracycline antibiotics (such as oxytetracycline, tetracycline or demeclocycline), aminoglycoside antibiotics (streptomycin, kanamycin A, gentamycin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribostamycin, bekanamycin, framycetin or paromomycin), macrolide antibiotics (such as erythromycin, Roxithromycin, clarithromycin or azithromycin) or other antibiotic (such as chloromycetin, ciclosporin or lincomycin) or its salt etc. in one or more,
Preferably, described cross-linking agent is selected from N, N '-methylene-bisacrylamide, N, N ' in-diallyl acrylamide, polyethyleneglycol diacrylate or divinylbenzene etc. one or more, be preferably N, N '-methylene-bisacrylamide;
Preferably, described initiator be selected from azo compound or per-compound one or both, preferably, described initiator be selected from azodiisobutyronitrile, dibenzoyl peroxide, Ammonium persulfate., potassium peroxydisulfate, sodium peroxydisulfate, hydrogen peroxide, ceric ammonium nitrate or ceric sulfate etc. one or more, be preferably potassium peroxydisulfate or Ammonium persulfate.;
Described catalyst be selected from tetramethylethylenediamine, DMA, ethylenediamine or triethylamine etc. one or more, be preferably tetramethylethylenediamine;
Described surfactant is selected from spans surfactant or one or both in the mixture that is made up of spans surfactant and Tweens surfactant, preferred sorbester p17 or sorbester p18, more preferably sorbester p17;
Preferably, described organic solvent is immiscible organic solvent with water; Preferably, described organic solvent be selected from mineral oil, vegetable oil, silicone oil, alkene, alcohol, aldehyde, amine, ether, ketone, terpene hydrocarbon, halogenated hydrocarbons, heterocycle compound, nitrogen-containing compound or sulfur-containing compound etc. one or more, preferred liquid paraffin or cyclohexane extraction.
Further, described reactant feed generates polymer microballoon by polyreaction, and preferably, the particle diameter of described polymer microballoon is 10-2000 micron, and preferable particle size is 50-1400 micron.
The present invention further provides a kind of preparation method of above-mentioned embolism materials, described preparation method obtains embolic particles by making polymer particles, magnetic metal ion and alkali substance reaction, comprises the following steps:
Step a1: make the monomer polymerization reaction take place containing unsaturated double-bond and anionic group generate polymer particles;
Step b1: the polymer particles obtained in step a1 is immersed in the solution containing magnetic metal ion, passes into protection gas in the solution;
Step c1: the solution that step b1 obtains is stirred, and add alkaline matter and react, obtain the embolic particles containing magnetisable material; Or
Described preparation method prepares embolic particles by magnetic particle and the monomer containing unsaturated double-bond and anionic group, comprises the following steps:
Magnetic particle is joined in the solution of the monomer containing unsaturated double-bond and anionic group, obtain the embolic particles containing magnetisable material by polyreaction;
Preferably, described magnetic particle adopts following methods preparation:
Step a2: pass into protection gas in containing the solution of magnetic metal ion;
Step b2: the solution that step a2 obtains is stirred, adds alkaline matter, obtain magnetic particle after reaction.
Further, described preparation method comprises the following steps:
Step a1: by water-soluble to the monomer containing unsaturated double-bond and anionic group, the biocompatible polymer material optionally containing hydroxyl, optional vinyl monomer, initiator, cross-linking agent and optional catalyst, under stirring, mixed liquor is joined in the organic solvent containing surfactant, 1 ~ 24h is reacted at 40 ~ 80 DEG C, polymer particles is obtained after preferably reacting 2 ~ 7h at 50 ~ 70 DEG C
Step b1: be immersed in by the polymer particles obtained in step a1 in the solution containing magnetic metal ion, pass into protection gas in the solution, soaks more than 10min, preferred 30-120min,
Step c1: at 60 ~ 100 DEG C, adds alkaline matter, adjust ph to 8 ~ 14 in the mixed liquor that step b1 obtains, and reaction more than 5min, preferred reaction 20-180min, obtain the embolic particles containing magnetisable material; Or,
Described preparation method comprises the following steps:
Step a2: pass into protection gas in containing the solution of magnetic metal ion,
Step b2: at 60 ~ 100 DEG C, stirs the solution that step a2 obtains, and adds alkaline matter, adjust ph to 8 ~ 14, and reaction more than 5min, preferred reaction 20-180min, obtain magnetic particle; After preferably adding alkali substance reaction, then add face finish material, after continuing reaction 15-180min, obtain magnetic particle,
Step c2: the magnetic particle obtained in step b2 is joined in the aqueous solution of the monomer containing unsaturated double-bond and anionic group, optional biocompatible polymer material, optional vinyl monomer, initiator, cross-linking agent and optional catalyst containing hydroxyl, under stirring, mixed liquor is joined in the organic solvent containing surfactant, at 40 ~ 80 DEG C, react 1 ~ 24h, after preferably reacting 2 ~ 7h at 50 ~ 70 DEG C, obtain the embolic particles containing magnetisable material;
Preferably, in described preparation method, comprise further after step c1 and step c2:
Steps d: be immersed in drug solution by the embolic particles obtained in step c1 or step c2, obtains the embolic particles of pastille.
Further, one or more in described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium plasma, preferably two or three, be more preferably the mixture of ferric ion and ferrous ion;
Preferably, described alkaline matter be selected from sodium hydroxide, potassium hydroxide, ammonia, diisopropanolamine (DIPA), isopropanolamine, Tetramethylammonium hydroxide or hydroxide second ammonium etc. one or more, be preferably sodium hydroxide, potassium hydroxide, diisopropanolamine (DIPA) or ammonia spirit;
Preferably, described face finish material be selected from oleic acid, lauric acid, citric acid, dodecyl sodium sulfate, glucosan or carboxylated Polyethylene Glycol etc. one or more, be preferably carboxylated Polyethylene Glycol;
Preferably, described protection gas be selected from nitrogen or noble gas one or more, be preferably nitrogen.
The present invention further provides above-mentioned embolism materials for the preparation for the treatment of tumor, such as hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma or malignant breast tumor, or vascular malformation or for the purposes in the medicine to stop blooding etc.
Compared with prior art, the present invention adopts at least can being had the following advantages by the embolism materials that MRI detects of the preparations such as nuclear magnetic resonance material:
1, of the present invention can be made by the embolism materials that MRI detects doctor in Embolization by MRI in real time, directly monitor suppository present position, accurate judgement is made to by the length of filling vessel segment, thromboembolism trend etc. that is whether fine and close and vascular embolization, be convenient to estimate effect of embolization, be also conducive to postoperative check.
2, complication is the principal risk of thromboembolism operation, maximum with the harm that dystopy thromboembolism and backflowing brings, doctor can monitor the position of suppository in real time by MRI, thus can take measures in time avoid dystopy thromboembolism and backflow, thus improves the efficacy and saferry of embolotherapy; In addition, accurate judgement thromboembolism terminal is the key of thromboembolism successful surgery, thromboembolism not exclusively can cause continuing of symptom or recurrence, inject too much suppository and then may cause dystopy thromboembolism, normal structure is caused to be damaged, and adopt embolism materials of the present invention make doctor after having injected suppository by MRI to detect suppository in endovascular filling situation, judge thromboembolism terminal more exactly, thus improve the efficacy and saferry of embolotherapy.
3, embolism materials of the present invention is adopted to make doctor can detect suppository distribution situation in vivo by MRI after thromboembolism, comprise suppository whether even in endovascular distribution, whether the distribution of suppository changes, whether degradable suppository there is degraded etc., thus be conducive to postoperative evaluation blood vessel by the degree of thromboembolism, for treatment provides guidance further.
What 4, prepared by the present invention can be can be used for clinical Therapy study by the embolism materials that MRI detects: directly can show suppository distributed in three dimensions in vivo by MRI, the thromboembolism position that the suppository of various dose, different materials and variable concentrations reaches and curative effect all can directly be embodied, thus be conducive to doctor and update embolization technique, improve the efficacy and safety of embolotherapy.
5, use the embolism materials that can be detected by MRI of the present invention can avoid patient because of X-radiological survey X the rasdiation damage that causes.
6, after adding medicine in embolism materials of the present invention, embolotherapy and Drug therapy can be made to play synergism, make doctor can utilize position and the density of the direct monitor and forecast suppository of MRI, realize the target administration function of medicine carrying suppository better, make medicine at local sustained release, maintain longer action time, higher local concentration, and reduce the toxic and side effects that medicine causes at other position of whole body.
7, the embolism materials that can be detected by MRI prepared of the present invention, preparation technology is simple, and cost is low, is applicable to large-scale industrial production, is conducive to clinical expansion and the application of product.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 is the optical microscope photograph of blank microsphere prepared by the embodiment of the present invention 1;
Fig. 2 is the optical microscope photograph of the embolism microball that can be detected by MRI prepared by the embodiment of the present invention 1;
Fig. 3 is the optical microscope photograph carrying the embolism microball of amycin prepared by the embodiment of the present invention 15;
Fig. 4 is the drug release profiles carrying the embolism microball of amycin prepared by the embodiment of the present invention 15;
Fig. 5 is the MRI vitro detection image of the embodiment of the present invention 1 blank microsphere prepared and the embolism microball that can be detected by MRI;
Fig. 6 is that the embolism microball that can be detected by MRI prepared of the embodiment of the present invention 1 is at the subcutaneous MRI image of mice;
Fig. 7 is year embolism microball of amycin and the MRI vitro detection image of blank microsphere prepared by the embodiment of the present invention 15.
Detailed description of the invention
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is conventional method.Medicine material used in following embodiment, reagent, material etc., if no special instructions, be commercially available purchase product.
Embodiment 1: the preparation of embolism materials
(1) by 0.45g acrylic acid, 0.55g2-acrylamide-2-methylpro panesulfonic acid, 0.027g N, N '-methylene-bisacrylamide, 0.024g potassium peroxydisulfate and 0.089g tetramethylethylenediamine are water-soluble, under stirring, mixed liquor is joined in the 40ml liquid paraffin containing 0.005g sorbester p17, at 55 DEG C of reaction 4h, collect obtained blank microsphere, this microsphere form under an optical microscope as shown in Figure 1;
(2) blank microsphere is immersed in containing in 0.14g ferric iron and the ferrous solution of 0.07g, passes into nitrogen in the solution, soak 60min;
(3) under 60 ~ 100 DEG C and stirring condition, add 8mol/L sodium hydroxide solution, adjust ph to 8 ~ 14 in system, reaction 60min, collect obtained embolism microball, this microsphere form under an optical microscope as shown in Figure 2.
Embodiment 2: the preparation of embolism materials
(1) in containing 0.34g ferric iron and the ferrous solution of 0.16g, nitrogen is passed into;
(2) under 100 DEG C of stirring conditions, add 3mol/L diisopropanol amine aqueous solution, adjust ph to 8 ~ 14 in system, reaction 120min, receives obtained magnetic particle;
(3) magnetic particle is joined containing 1g acrylic acid, 0.2g polyvinyl alcohol, 0.007g N, in the aqueous solution of N '-methylene-bisacrylamide, 0.01g potassium peroxydisulfate and 0.005g tetramethylethylenediamine, mixed liquor is joined in the 50ml liquid paraffin containing 0.04g sorbester p17, at 65 DEG C of reaction 5h, collect obtained embolism microball.
Embodiment 3: the preparation of embolism materials
(1) by 1g acrylic acid, 0.0002g N, N '-methylene-bisacrylamide, 0.0003g potassium peroxydisulfate and 0.0005g tetramethylethylenediamine are water-soluble, under stirring, are joined by mixed liquor in the 40ml liquid paraffin containing 0.028g sorbester p17, at 50 DEG C of reaction 4h, collect obtained blank microsphere;
(2) blank microsphere is immersed in containing in 9.8g ferric iron and the ferrous solution of 4.9g, passes into nitrogen in the solution, soak 60min;
(3) under 60 ~ 100 DEG C and stirring condition, add 25%w/w ammonia spirit, adjust ph to 8 ~ 14 in system, reaction 60min, collects obtained embolism microball.
Embodiment 4: the preparation of embolism materials
(1) in the solution containing 0.16g ferric ion and 0.09g divalent cobalt ion, nitrogen is passed into;
(2) under 100 DEG C of stirring conditions, add 3mol/L diisopropanol amine aqueous solution, adjust ph to 8 ~ 14 in system, reaction 120min, adds carboxylated Polyethylene Glycol subsequently, continues reaction 60min, collects obtained magnetic particle;
(3) magnetic particle is joined 2-acrylamide-2-methylpro panesulfonic acid, 0.167g polyvinyl alcohol, the 0.001g N containing 1g, in the aqueous solution of N '-methylene-bisacrylamide, 0.007g potassium peroxydisulfate and 0.003g tetramethylethylenediamine, mixed liquor is joined in the 50ml liquid paraffin containing 0.022g sorbester p17, at 65 DEG C of reaction temperature reaction 4h, collect obtained embolism microball.
Embodiment 5: the preparation of embolism materials
(1) by 1g acrylic acid, 0.33g acrylamide, 0.008g N, N '-methylene-bisacrylamide, 0.015g Ammonium persulfate. and 0.01g tetramethylethylenediamine are water-soluble, under stirring, mixed liquor is joined in the 40ml liquid paraffin containing 0.04g sorbester p17, at 70 DEG C of reaction 2h, collect obtained blank microsphere;
(2) blank microsphere is immersed in the solution containing 0.047g ferric iron and 0.023g bivalent manganese, passes into nitrogen in the solution, soak 120min;
(3) under 60 ~ 100 DEG C and stirring condition, add 10mol/L potassium hydroxide solution, adjust ph to 8 ~ 14 in system, reaction 60min, collects obtained embolism microball.
Embodiment 6: the preparation of embolism materials
(1) in containing 0.64g ferric iron and the ferrous solution of 0.36g, nitrogen is passed into;
(2) under 70 DEG C of stirring conditions, add 25%w/w ammonia spirit, adjust ph to 8 ~ 14 in system, reaction 50min, collects obtained magnetic particle;
(3) magnetic particle is joined containing 0.6g2-acrylamide-2-methylpro panesulfonic acid, 0.4g2-acrylamide-2-methylpro panesulfonic acid sodium, 5g methacrylic acid-2-hydroxy methacrylate, 0.07g N, in the aqueous solution of N '-methylene-bisacrylamide and 0.07g Ammonium persulfate., mixed liquor is joined in the 100ml liquid paraffin containing 3g sorbester p17, at 75 DEG C of reaction 7h, collect obtained embolism microball.
Embodiment 7: the preparation of embolism materials
(1) by 1g acrylic acid, 0.1g methacrylic acid-2-hydroxy methacrylate, 0.0004g N, N '-methylene-bisacrylamide, 0.001g potassium peroxydisulfate and 0.001g tetramethylethylenediamine are water-soluble, under stirring, mixed liquor is joined in the 80ml liquid paraffin containing 2.5 sorbester p18s, at 80 DEG C of reaction 3h, collect obtained blank microsphere;
(2) blank microsphere is immersed in containing in 15g ferric iron and the ferrous solution of 15g, passes into nitrogen in the solution, soak 60min;
(3) under 60 ~ 100 DEG C and stirring condition, add 10mol/L sodium hydroxide solution, adjust ph to 8 ~ 14 in system, reaction 120min, collects obtained embolism microball.
Embodiment 8: the preparation of embolism materials
(1) nitrogen is being passed into containing in 0.0028g ferric iron, 0.0003g trivalent dysprosium and the ferrous solution of 0.0028g;
(2) under 75 DEG C of stirring conditions, add 25%w/w ammonia spirit, adjust ph to 8 ~ 14 in system, reaction 50min, collects obtained magnetic particle;
(3) magnetic particle is joined containing 1g acrylic acid, 0.0003g N, in the aqueous solution of N '-methylene-bisacrylamide and 0.0005g Ammonium persulfate., mixed liquor is joined in the 60ml cyclohexane extraction containing 1.5g sorbester p17, at 48 DEG C of reaction 6h, collect obtained embolism microball.
Embodiment 9: the preparation of embolism materials
(1) in the solution containing 0.0003g ferric iron and 0.0002g bivalent manganese, nitrogen is passed into;
(2) under 60 DEG C of stirring conditions, add 3mol/L diisopropanol amine aqueous solution, adjust ph to 8 ~ 14 in system, reaction 20min, adds carboxylated Polyethylene Glycol subsequently, continues reaction 15min, receives obtained magnetic particle;
(3) magnetic particle is joined containing 1g sodium acrylate, 2g polyvinyl alcohol, 0.2g acrylamide, 0.043g N, in the aqueous solution of N '-methylene-bisacrylamide, 0.051g potassium peroxydisulfate and 0.1g tetramethylethylenediamine, mixed liquor is joined in the 10ml liquid paraffin containing 0.1g sorbester p17, at 40 DEG C of reaction 1h, collect obtained embolism microball.
Embodiment 10: the preparation of embolism materials
(1) in the solution containing 0.005g ferric ion and 0.002g divalent cobalt ion, nitrogen is passed into;
(2) under 80 DEG C of stirring conditions, add 3mol/L diisopropanol amine aqueous solution, adjust ph to 8 ~ 14 in system, reaction 100min, adds carboxylated Polyethylene Glycol subsequently, continues reaction 180min, collects obtained magnetic particle;
(3) magnetic particle is joined 2-acrylamide-2-methylpro panesulfonic acid, the acrylic acid of 0.5g, 0.1g polyvinyl alcohol, 7g acrylamide, the 0.075g N containing 0.5g, in the aqueous solution of N '-methylene-bisacrylamide, 0.08g potassium peroxydisulfate and 0.139g tetramethylethylenediamine, mixed liquor is joined in the 30ml liquid paraffin containing 1g sorbester p17, at 45 DEG C of reaction temperature reaction 24h, collect obtained embolism microball.
Embodiment 11: the preparation of embolism materials
(1) by 0.5g acrylic acid, 0.5g sodium acrylate, 1g polyvinyl alcohol, 3g methacrylic acid-2-hydroxy methacrylate, 0.05g N, N '-methylene-bisacrylamide and 0.06g Ammonium persulfate. water-soluble, under stirring, mixed liquor is joined in the 25ml liquid paraffin containing 0.5g sorbester p17, at 60 DEG C of reaction 10h, collect obtained blank microsphere;
(2) blank microsphere is immersed in containing in 2g trivalent dysprosium, 19g ferric iron and the ferrous solution of 19g, passes into nitrogen in the solution, soak 80min;
(3) under 60 ~ 100 DEG C and stirring condition, add 10mol/L potassium hydroxide solution, adjust ph to 8 ~ 14 in system, reaction 180min, collects obtained embolism microball.
Embodiment 12: the preparation of embolism materials
(1) in containing 0.0007g ferric iron and the ferrous solution of 0.0003g, nitrogen is passed into;
(2) under 90 DEG C of stirring conditions, add 25%w/w ammonia spirit, adjust ph to 8 ~ 14 in system, reaction 180min, adds carboxylated Polyethylene Glycol subsequently, continues reaction 30min, collects obtained magnetic particle;
(3) magnetic particle is joined containing 0.2g2-acrylamide-2-methylpro panesulfonic acid, 0.3g2-acrylamide-2-methylpro panesulfonic acid sodium, 0.2g acrylic acid, 0.3g sodium acrylate, 0.12g methacrylic acid-2-hydroxy methacrylate, 0.5g acrylamide, 0.01g N, in the aqueous solution of N '-methylene-bisacrylamide, 0.038g sodium peroxydisulfate and 0.05g tetramethylethylenediamine, mixed liquor is joined in the 3ml liquid paraffin containing 0.01g sorbester p17, at 47 DEG C of reaction 15h, collect obtained embolism microball.
Embodiment 13: the preparation of embolism materials
(1) by 1g acrylic acid, 0.8g polyvinyl alcohol, 1g methacrylic acid-2-hydroxy methacrylate, 0.03g N, N '-methylene-bisacrylamide, 0.045g potassium peroxydisulfate and 0.08g tetramethylethylenediamine are water-soluble, under stirring, mixed liquor is joined in the 7ml cyclohexane extraction containing 0.03g sorbester p18, at 58 DEG C of reaction 3h, collect obtained blank microsphere;
(2) blank microsphere is immersed in the solution containing 8g ferric iron and 7g bivalent manganese, passes into nitrogen in the solution, soak 30min;
(3) under 60 ~ 100 DEG C and stirring condition, add 10mol/L sodium hydroxide solution, adjust ph to 8 ~ 14 in system, reaction 20min, collects obtained embolism microball.
Embodiment 14: the preparation of embolism materials
(1) by 1g acrylic acid, 0.5g polyvinyl alcohol, 10g acrylamide, 0.1g N, N '-methylene-bisacrylamide, 0.09g potassium peroxydisulfate and 0.2g tetramethylethylenediamine are water-soluble, under stirring, mixed liquor is joined in the 75ml liquid paraffin containing 2g sorbester p18, at 63 DEG C of reaction 4h, collect obtained blank microsphere;
(2) blank microsphere is immersed in containing in 14g ferric iron and the ferrous solution of 6g, passes into nitrogen in the solution, soak 10min;
(3) under 60 ~ 100 DEG C and stirring condition, add 10mol/L sodium hydroxide solution, adjust ph to 8 ~ 14 in system, reaction 5min, collects obtained embolism microball.
Embodiment 15: the medicine carrying of embolism materials and release are tested
The embolism microball containing magnetic particle 1ml embodiment 1 prepared is immersed in the medicinal liquid containing 0.1g doxorubicin hydrochloride.After measured, the drug loading of microsphere medicine carrying 24h is 42.0mg/ml.Carry the embolism microball form under an optical microscope of amycin as shown in Figure 3.
T-shaped tube method is adopted to measure the release in vitro of above-mentioned medicine carrying microballoons.In T-shaped pipe, add the phosphate buffer of 200mlpH7.4 as release medium, the mobility of buffer is 50ml/min, and bath temperature is 37 DEG C.Embolism microball 1ml being carried amycin is placed in the bottom of T-shaped pipe, at 0.5h, 1h, 2h, 4h, 6h, 24h, 48h, 72h and 120h, take out 5ml release medium respectively and supply isothermal, isopyknic fresh dissolution medium immediately, under 233nm wavelength, measure absorbance, calculate release amount according to standard curve.Carry the drug release profiles of the embolism microball of amycin as shown in Figure 4.As can be seen from Figure 4, the embolism microball carrying amycin is very fast in front 6h rate of release, during 6h cumulative release about 2.6%, 120h time cumulative release be about 5%.
Embodiment 16: the medicine carrying of embolism materials and release are tested
The microsphere containing magnetic particle 1ml embodiment 2 prepared is immersed in the medicinal liquid containing 0.005g Sunitinib malate.After measured, the drug loading of microsphere medicine carrying 24h is 4.28mg/ml.
T-shaped tube method is adopted to measure the release in vitro of above-mentioned medicine carrying microballoons.In T-shaped pipe, add the phosphate buffer of 200mlpH7.4 as release medium, buffer mobility is 50ml/min, and bath temperature is 37 DEG C.Embolism microball 1ml being carried Sutent is placed in the bottom of T-shaped pipe, in 0.5h, 1h, 2h, 4h, 6h, 24h, 48h, 72h, 96h, 120h, 144h, 168h and 192h, take out 5ml release medium respectively and supply isothermal, isopyknic fresh dissolution medium immediately, under 427nm wavelength, measure absorbance, calculate release amount according to standard curve.Result shows, cumulative release about 16.5% when carrying the embolism microball 192h of Sutent.
Embodiment 17: the medicine carrying release experiment of embolism materials
The microsphere containing magnetic particle 1ml embodiment 3 prepared is immersed in the medicinal liquid containing 0.02g Sorafenib Tosylate.After measured, the drug loading of microsphere medicine carrying 24h is 10.2mg/ml.
T-shaped tube method is adopted to measure the release in vitro of above-mentioned medicine carrying microballoons.In T-shaped pipe, add the phosphate buffer of 200mlpH7.4 as release medium, buffer mobility is 50ml/min, and bath temperature is 37 DEG C.Embolism microball 1ml being carried Sorafenib is placed in the bottom of T-shaped pipe, in 0.5h, 1h, 2h, 4h, 6h, 24h, 48h, 72h, 96h, 120h, 144h and 168h, take out 5ml release medium respectively and supply isothermal, isopyknic fresh dissolution medium immediately, under 265nm wavelength, measure absorbance, calculate release amount according to standard curve.Result shows, cumulative release about 12.5% when carrying the embolism microball 168h of Sorafenib.
Embodiment 18: the medicine carrying of embolism materials and release are tested
The microsphere containing magnetic particle 1ml embodiment 4 prepared is immersed in the medicinal liquid containing 0.5g lidocaine hydrochloride.After measured, the drug loading of microsphere medicine carrying 24h is 120.3mg/ml.
T-shaped tube method is adopted to measure the release in vitro of above-mentioned medicine carrying microballoons.In T-shaped pipe, add the phosphate buffer of 200mlpH7.4 as release medium, buffer mobility is 50ml/min, and bath temperature is 37 DEG C.Embolism microball 1ml being carried lignocaine is placed in the bottom of T-shaped pipe, in 0.25h, 0.5h, 0.75h, 1h, 2h, 3.5h, 4.5h, 5.5h, 6.5h and 24h, take out 5ml release medium respectively and supply isothermal, isopyknic fresh dissolution medium immediately, under 261nm wavelength, measure absorbance, calculate release amount according to standard curve.Result shows, cumulative release about 26% when carrying the embolism microball 24h of lignocaine.
Embodiment 19: the medicine carrying of embolism materials and release are tested
The microsphere containing magnetic particle 1ml embodiment 5 prepared is immersed in the medicinal liquid containing 0.5g Bleomycin A5 hydrochloride..After measured, the drug loading of microsphere medicine carrying 24h is 100.1mg/ml.
T-shaped tube method is adopted to measure the release in vitro of above-mentioned medicine carrying microballoons.In T-shaped pipe, add the phosphate buffer of 200mlpH7.4 as release medium, buffer mobility is 50ml/min, and bath temperature is 37 DEG C.Embolism microball 1ml being carried Bleomycin A5 is placed in the bottom of T-shaped pipe, in 0.25h, 0.5h, 0.75h, 1h, 2h, 3.5h, 4.5h, 5.5h, 6.5h and 24h, take out 5ml release medium respectively and supply isothermal, isopyknic fresh dissolution medium immediately, under 291nm wavelength, measure absorbance, calculate release amount according to standard curve.Result shows, cumulative release about 35% when carrying the embolism microball 24h of Bleomycin A5.
The external MRI imaging of embolism materials
The microsphere containing magnetic particle of embodiment 1 preparation is carried out to the external image checking of MRI: prepare 2% agar hot solution, pour in culture dish, liquid level thickness is made to be 1.5cm, after solution cooling forms gel, be placed on agar surface respectively by blank microsphere with containing the microsphere of magnetic particle, again pour agar hot solution that thickness is 1cm into and cool.Scan under surface plate being placed in 3T MRI, testing result as shown in Figure 5.Embolism microball (the left side can detected by MRI is shown respectively in Fig. 5, black) and blank microsphere (right side, white) MRI vitro detection image (number of both sides microsphere is respectively 1,2,3,4,5 from top to bottom), as can be seen from Figure 5, the present invention adopts the embolism materials of the preparations such as nuclear magnetic resonance material directly, exactly can be detected by MRI.
The subcutaneous MRI imaging of mice of embolism materials
That prepares from embodiment 1 contains the microsphere of magnetic particle the microsphere sieving out 100-300 μm, and by microsphere suspendible in 1% carboxymethylcellulose sodium solution, injection mice is subcutaneous.Scan under mice being placed in 3T MRI, testing result as shown in Figure 6.The external white bright spot of Fig. 6 small mouse is vitamin E capsule (for indicating injection site), and white arrow also indicates microsphere injections position.The embolism microball containing magnetic particle of result display mouse subcutaneous injection can be detected by MRI.
The external MRI imaging of embolism materials
The embolism microball of year amycin prepared by embodiment 15 is carried out to the vitro detection of MRI, and with the blank microsphere of embodiment 1 preparation in contrast.Prepare 2% agar hot solution, pour in culture dish, make liquid level thickness be 1.5cm, formed after gel until solution cooling, blank microsphere and the embolism microball that carries amycin are placed on agar surface respectively, again pour agar hot solution that thickness is 1cm into and cool.Scan under surface plate being placed in 3T MRI, testing result as shown in Figure 7.Embolism microball (the left side of carrying amycin is respectively illustrated in Fig. 7, black) and blank microsphere (right side, white) MRI vitro detection image (number of both sides microsphere is respectively 1,2,3,4,5 from top to bottom), as can be seen from Figure 7, the present invention adopt the preparation such as nuclear magnetic resonance material carry amycin embolism materials can clear by MRI, be directly detected.
Specific description of embodiments of the present invention does not above limit the present invention, and those skilled in the art can make various change or distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (51)
1. an embolism materials, it is generated by polyreaction by reactant feed, and described reactant feed comprises:
Wherein, described nuclear magnetic resonance material is calculated with the gauge of magnetic metal element, and described reactant feed generates polymer by polyreaction, on the anionic group that described nuclear magnetic resonance material is bonded to described polymer or dispersion in the polymer.
2. embolism materials according to claim 1, is characterized in that, described reactant feed comprises:
3. embolism materials according to claim 1, is characterized in that, described reactant feed comprises:
4. embolism materials according to any one of claim 1 to 3, is characterized in that, described nuclear magnetic resonance material is oxide or the magnetic metal ion of magnetic metal element;
The described monomer containing unsaturated double-bond and anionic group be selected from acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid, 2-acrylamide-2-methylpro panesulfonic acid salt, sodium allylsulfonate, methacrylic acid or methacrylate one or more;
The described macromolecular material containing hydroxyl be selected from polyvinyl alcohol, alginic acid, chitosan, cellulose or amylose one or more;
Described vinyl monomer be selected from acrylamide, acrylonitrile, acrylate or methacrylate one or more;
Described cross-linking agent is selected from N, N '-methylene-bisacrylamide, N, N ' one or more in-diallyl acrylamide, polyethyleneglycol diacrylate or divinylbenzene;
Described catalyst be selected from tetramethylethylenediamine, DMA, ethylenediamine or triethylamine one or more;
Described initiator be selected from azo compound or per-compound one or both;
Described surfactant is selected from spans surfactant or one or both in the mixture that is made up of spans surfactant and Tweens surfactant;
Described organic solvent is immiscible organic solvent with water.
5. embolism materials according to claim 4, is characterized in that, the oxide of described magnetic metal element is selected from Fe
3o
4, Fe
2o
3, MnFe
2o
4, CoFe
2o
4, NiFe
2o
4or one or more in the oxide of holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium.
6. embolism materials according to claim 4, is characterized in that, one or more in described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium ion.
7. embolism materials according to claim 6, is characterized in that, in described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium ion two or three.
8. the embolism materials according to claim 6 or 7, is characterized in that, described magnetic metal ion is the mixture of ferric ion and ferrous ion.
9. embolism materials according to claim 4, it is characterized in that, the described monomer containing unsaturated double-bond and anionic group be selected from acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid or 2-acrylamide-2-methylpro panesulfonic acid salt one or more.
10. embolism materials according to claim 9, it is characterized in that, the described monomer containing unsaturated double-bond and anionic group is the mixture be made up of acrylic acid and acrylates, the mixture be made up of acrylic acid and 2-acrylamide-2-methylpro panesulfonic acid, the mixture be made up of 2-acrylamide-2-methylpro panesulfonic acid and 2-acrylamide-2-methylpro panesulfonic acid salt or the mixture that is made up of acrylic acid, acrylates, 2-acrylamide-2-methylpro panesulfonic acid and 2-acrylamide-2-methylpro panesulfonic acid salt.
11. embolism materials according to claim 9 or 10, it is characterized in that, described acrylates is sodium acrylate, and described 2-acrylamide-2-methylpro panesulfonic acid salt is 2-acrylamide-2-methylpro panesulfonic acid sodium.
12. embolism materials according to claim 4, it is characterized in that, described anionic group be selected from carboxylate anion, azochlorosulfonate acid anion, sulfate anion, phosphonate radical anion, nitrate anion, carbonate anion or phosphate radical anion one or more.
13. embolism materials according to claim 12, is characterized in that, described anionic group is carboxylate anion or azochlorosulfonate acid anion.
14. embolism materials according to claim 4, is characterized in that, the described macromolecular material containing hydroxyl is polyvinyl alcohol.
15. embolism materials according to claim 4, is characterized in that, described vinyl monomer is acrylamide or methacrylic acid-2-hydroxy methacrylate.
16. embolism materials according to claim 4, is characterized in that, described cross-linking agent is N, N '-methylene-bisacrylamide.
17. embolism materials according to claim 4, is characterized in that, described catalyst is tetramethylethylenediamine.
18. embolism materials according to claim 4, it is characterized in that, described initiator be selected from azodiisobutyronitrile, dibenzoyl peroxide, Ammonium persulfate., potassium peroxydisulfate, sodium peroxydisulfate, hydrogen peroxide, ceric ammonium nitrate or ceric sulfate one or more.
19. embolism materials according to claim 18, is characterized in that, described initiator is potassium peroxydisulfate or Ammonium persulfate..
20. embolism materials according to claim 4, is characterized in that, described surfactant is sorbester p17 or sorbester p18.
21. embolism materials according to claim 20, is characterized in that, described surfactant is sorbester p17.
22. embolism materials according to claim 4, is characterized in that, described organic solvent be selected from mineral oil, vegetable oil, silicone oil, alkene, alcohol, aldehyde, amine, ether or ketone one or more.
23. embolism materials according to claim 22, is characterized in that, described organic solvent is liquid paraffin or cyclohexane extraction.
24. embolism materials according to any one of claim 1 to 3, is characterized in that, described embolism materials comprises medicine further, and the drug loading of described embolism materials is 0-120.3mg/ml.
25. embolism materials according to claim 24, is characterized in that, the drug loading of described embolism materials is 10.2-100.1mg/ml.
26. embolism materials according to claim 24, is characterized in that, described medicine be selected from antitumor drug, local anaesthesia medicine, antipyretic-antalgic anti-inflammatory agent thing or antibiotic medicine one or more.
27. embolism materials according to claim 26, it is characterized in that, described antitumor drug be selected from amycin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel, Docetaxel, 5-fluorouracil, Bleomycin A5, Sutent, Sorafenib, gefitinib, imatinib, PTK787 or its salt one or more.
28. embolism materials according to claim 26, it is characterized in that, described local anaesthesia medicine be selected from procaine, chloroprocaine, hydroxyprocaine, tetracaine, parethoxycaine, empty Tuo Kayin, dimethocaine, lignocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, supernatural power caine, quinisocaine, phenacaine or its salt one or more.
29. embolism materials according to claim 26, it is characterized in that, described antipyretic-antalgic anti-inflammatory agent thing be selected from aspirin, magnesium salicylate, sodium salicylate, choline magnesium trisalicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, fenoprofen, naproxen, nabumetone, piroxicam, Phenylbutazone, acetaminophen, diclofenac, venlofen, ketone ibuprofen, ketorolac, four clofenamic acides, sulindac or tolmetin one or more.
30. embolism materials according to claim 26, it is characterized in that, described antibiotic medicine is selected from penicillin, oxacillin sodium, ampicillin, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid, sulbactam, oxytetracycline, tetracycline, demeclocycline, streptomycin, kanamycin A, gentamycin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribostamycin, bekanamycin, framycetin, paromomycin, erythromycin, Roxithromycin, clarithromycin, azithromycin, chloromycetin, ciclosporin, one or more in lincomycin or its salt.
31. embolism materials according to any one of claim 1 to 3, is characterized in that, described reactant feed generates polymer microballoon by polyreaction.
32. embolism materials according to claim 31, is characterized in that, the particle diameter of described polymer microballoon is 10-2000 micron.
33. embolism materials according to claim 32, is characterized in that, the particle diameter of described polymer microballoon is 50-1400 micron.
The preparation method of 34. 1 kinds of embolism materials according to any one of claims 1 to 33, described preparation method obtains embolic particles by making polymer particles, magnetic metal ion and alkali substance reaction, comprises the following steps:
Step a1: by water-soluble to the monomer containing unsaturated double-bond and anionic group, the biocompatible polymer material optionally containing hydroxyl, optional vinyl monomer, initiator, cross-linking agent and optional catalyst, under stirring, mixed liquor is joined in the organic solvent containing surfactant, polymer particles is obtained react 1 ~ 24h at 40 ~ 80 DEG C after
Step b1: be immersed in by the polymer particles obtained in step a1 in the solution containing magnetic metal ion, pass into protection gas in the solution, soaks more than 10min,
Step c1: at 60 ~ 100 DEG C, adds alkaline matter, adjust ph to 8 ~ 14 in the mixed liquor that step b1 obtains, and reaction more than 5min, obtains the embolic particles containing magnetisable material.
35. preparation methoies according to claim 34, is characterized in that, in described step a1, obtain polymer particles after reacting 2 ~ 7h at 50 ~ 70 DEG C.
36. preparation methoies according to claim 34, is characterized in that, in described step b1, soak 30-120min.
37. preparation methoies according to claim 34, is characterized in that, in described step c1, and reaction 20-180min.
The preparation method of 38. 1 kinds of embolism materials according to any one of claims 1 to 33, described preparation method prepares embolic particles by magnetic particle and the monomer containing unsaturated double-bond and anionic group, comprises the following steps:
Step a2: pass into protection gas in containing the solution of magnetic metal ion,
Step b2: at 60 ~ 100 DEG C, stirs the solution that step a2 obtains, and adds alkaline matter, adjust ph to 8 ~ 14, and reaction more than 5min, obtains magnetic particle,
Step c2: the magnetic particle obtained in step b2 is joined in the aqueous solution of the monomer containing unsaturated double-bond and anionic group, optional biocompatible polymer material, optional vinyl monomer, initiator, cross-linking agent and optional catalyst containing hydroxyl, under stirring, mixed liquor is joined in the organic solvent containing surfactant, react 1 ~ 24h at 40 ~ 80 DEG C after, obtain the embolic particles containing magnetisable material.
39., according to preparation method according to claim 38, is characterized in that, in described step b2, and reaction 20-180min.
40., according to preparation method according to claim 38, is characterized in that, in described step b2, after adding alkali substance reaction, then add face finish material, obtain magnetic particle after continuing reaction 15-180min.
41. preparation methoies according to claim 40, is characterized in that, described face finish material be selected from oleic acid, lauric acid, citric acid, dodecyl sodium sulfate, glucosan or carboxylated Polyethylene Glycol one or more.
42., according to preparation method according to claim 38, is characterized in that, in described step c2, obtain the embolic particles containing magnetisable material at 50 ~ 70 DEG C after reacting 2 ~ 7h.
43. preparation methoies according to any one of claim 34 to 42, is characterized in that, comprise further after step c1 and step c2:
Steps d: be immersed in drug solution by the embolic particles obtained in step c1 or step c2, obtains the embolic particles of pastille.
44. preparation methoies according to any one of claim 34 to 42, is characterized in that, one or more in described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium ion;
Described alkaline matter be selected from sodium hydroxide, potassium hydroxide, ammonia, diisopropanolamine (DIPA), isopropanolamine, Tetramethylammonium hydroxide or hydroxide second ammonium one or more;
Described protection gas be selected from nitrogen or noble gas one or more.
45. preparation methoies according to claim 44, is characterized in that, in described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium ion two or three.
46. preparation methoies according to claim 45, is characterized in that, described magnetic metal ion is the mixture of ferric ion and ferrous ion.
47. preparation methoies according to claim 44, is characterized in that, described alkaline matter is sodium hydroxide, potassium hydroxide, diisopropanolamine (DIPA) or ammonia spirit.
48. preparation methoies according to claim 41, is characterized in that, described face finish material is carboxylated Polyethylene Glycol.
49. preparation methoies according to claim 44, is characterized in that, described protection gas is nitrogen.
50. embolism materials according to any one of claims 1 to 33 are for the preparation for the treatment of tumor or vascular malformation or for the purposes in the medicine that stops blooding.
51. purposes according to claim 50, is characterized in that, described tumor is hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma or malignant breast tumor.
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| CN108671262B (en) * | 2018-07-06 | 2021-09-24 | 华南师范大学 | Embolic agent and preparation method and application thereof |
| CN112755238A (en) * | 2019-12-31 | 2021-05-07 | 北京大学 | Embolic material composition and preparation method and application thereof |
| CN112569878B (en) * | 2020-01-21 | 2021-09-28 | 苏州恒瑞宏远医疗科技有限公司 | Equipment for preparing polyvinyl alcohol embolism microsphere with uniform grain diameter and production process thereof |
| CN112972754B (en) * | 2021-02-24 | 2022-07-19 | 苏州微尺度科技有限公司 | Visual fucoidin embolism microsphere and preparation method thereof |
| CN113018461B (en) * | 2021-03-09 | 2022-07-26 | 南京邮电大学 | Fucoidin embolism microsphere capable of magnetic resonance imaging and preparation method thereof |
| CN113304305A (en) * | 2021-04-27 | 2021-08-27 | 宁波绿糖生物科技有限公司 | Glucan microsphere and preparation method and application thereof |
| CN113521378A (en) * | 2021-07-20 | 2021-10-22 | 上海益思妙医疗器械有限公司 | Preparation method of porous microspheres, microsphere embolic agent obtained by preparation method and application of microsphere embolic agent |
| CN115590824A (en) * | 2022-11-11 | 2023-01-13 | 浙江大学（Cn） | Polyvinyl alcohol embolism microsphere with developer and preparation method and application thereof |
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Effective date of registration: 20211227 Address after: 100083 Room 606, 6th floor, building 9, 35 Huayuan North Road, Haidian District, Beijing Patentee after: HYGEA MEDICAL TECHNOLOGY Co.,Ltd. Address before: 100191 Department of pharmacy, Department of medicine, Peking University, No. 38 Xueyuan Road, Haidian District, Beijing Patentee before: Peking University |