CN103550834A - Embolism material composition as well as preparation method and use thereof - Google Patents

Embolism material composition as well as preparation method and use thereof Download PDF

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CN103550834A
CN103550834A CN201310512955.0A CN201310512955A CN103550834A CN 103550834 A CN103550834 A CN 103550834A CN 201310512955 A CN201310512955 A CN 201310512955A CN 103550834 A CN103550834 A CN 103550834A
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weight portion
embolism
gelatin
polyvinyl alcohol
microcapsule
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CN103550834B (en
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范田园
卢晓静
孟文静
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Hygea Medical Technology Co Ltd
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Peking University
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Abstract

The invention provides an embolism material composition as well as preparation method and use thereof, the embolism material composition is prepared from reactant raw materials, wherein the reactant raw materials comprise a biocompatibility material, a roentgenopaque substance and a magnetic resonance imaging substance, the roentgenopaque substance and the magnetic resonance imaging (MRI) substance are covered by the biocompatibility material. The embolism material composition not only can be directly detected by an X-ray image device, but also can be directly detected by the MRI, so that a doctor can select a detection method according to self condition of a patient and the medical device condition.

Description

A kind of embolism materials composition and method of making the same and purposes
Technical field
The invention belongs to interventional medicine field, be specifically related to a kind of embolism materials composition and method of making the same and purposes.
Background technology
Intervention embolization refers under the guiding of medical imaging device, and suppository, by accurate apparatuses such as special seal wire, conduits, is introduced to human body and carried out topical therapeutic.Thromboembolism therapy has obtained good curative effect at aspects such as treatment hysteromyoma, hepatocarcinoma, renal carcinoma, hemangioma, vascular malformation and hemostasis, becomes the alternative medicine of part operative treatment.
The suppository of clinical practice at present, as polyvinyl alcohol irregular particle type or microsphere type embolic agent, gelfoam irregular particle type or microsphere type embolic agent etc. all can not (be comprised digital outline contrast machine (Digital Subtraction Angiography by X ray image equipment, DSA) and computed tomography (Computed Tomography, and nuclear magnetic resonance (Magnetic Resonance Imaging, MRI) direct-detection CT)).In practical application, can only check flowing of contrast agent and indirectly infer position and the thromboembolism terminal at suppository place by DSA.A nearest clinical research shows, judges that by this method uterine artery, by the case of complete thromboembolism, has 20% not reach complete thromboembolism, and postoperative MRI checks that the part uterine artery that shows these patients still has blood to supply.Therefore, this indirect determination methods can not judge position and the thromboembolism terminal at suppository place in time, exactly, has affected the efficacy and saferry of embolotherapy.
In order to carry out the direct-detection under X ray image equipment to suppository, in prior art, disclose some roentgenopaque embolism materials, yet there is ionizing radiation in X-ray examination, be especially unfavorable for young woman to carry out thromboembolism and the check of hysteromyoma.
Nuclear magnetic resonance (MRI) is a kind of Novel medical diagnostic means growing up in recent decades, is a kind of methods for clinical diagnosis safely, fast and accurately.Be applicable to the diagnosis of various diseases, some are suitable for the disease of embolotherapy to comprise diagnosis, as: arteriovenous malformotion, hepatocarcinoma and hysteromyoma etc.MRI has higher room and time resolution, and good normal structure and the contrast between pathological tissues, compare and there is no ionizing radiation with X ray detection technique, and developed into can Real-time Collection high-definition picture degree.But the defect of MRI is can not be for being equipped with the patient of electricity, magnetic and mechanical active implant (as cardiac pacemaker, nerve stimulator, cochlear implantation prosthesis or metal ocular prosthesis etc.) in body.
Therefore, how to provide a kind of can again can be by the embolism materials of MRI direct-detection to for patient provides more selection, become this area problem demanding prompt solution by X ray image equipment direct-detection.
Summary of the invention
For the problems referred to above, one object of the present invention is to provide a kind of embolism materials compositions, this embolism materials compositions can not only be by X ray image equipment direct-detection, and can, by MRI direct-detection, be convenient to doctor and select detection method according to patient's self-condition and armarium condition.
Another object of the present invention is to provide a kind of preparation method of embolism materials compositions.
A further object of the present invention is to provide a kind of purposes of embolism materials compositions.
For achieving the above object, the invention provides a kind of embolism materials compositions, it is made by reactant feed, described reactant feed comprises: biocompatible materials, roentgenopaque material and nuclear magnetic resonance material, in described embolism materials compositions, roentgenopaque material and nuclear magnetic resonance material are wrapped up by biocompatible materials.
Further, described reactant feed comprises: 1 weight portion biocompatible materials, the roentgenopaque material of 0.5-10 weight portion, 0.2-5 weight portion nuclear magnetic resonance material and 0-6 weight portion medicine; Wherein, described medicine is wrapped up by biocompatible materials.
Further, described embolism materials compositions is spherical and erose microgranule, preferably microcapsule or microsphere;
Preferably, the particle diameter of described microgranule is 10-2000 μ m, can be according to actual needs, and selecting the particle diameter of microgranule is 50-100 μ m, 100-300 μ m, 300-500 μ m, 500-700 μ m, 700-900 μ m, 900-1200 μ m or 1200-1500 μ m etc.
Further, described biocompatible materials be selected from polyvinyl alcohol, alginic acid, alginate, chitosan, gelatin, arabic gum, starch, starch derivatives, cellulose, cellulose derivative, polylactic acid or the copolymer that formed by lactic acid and hydroxyacetic acid etc. in one or more;
Preferably, described roentgenopaque material is selected from one or both in roentgenopaque oily liquids or roentgenopaque solid, preferred roentgenopaque oily liquids, more preferably one or both in iodized oil or iofendylate; Described roentgenopaque solid is selected from one or both in tantalum powder or barium sulfate;
Preferably, described nuclear magnetic resonance material is selected from one or more in the compound of magnetic metal elemental iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium; Preferably, described nuclear magnetic resonance material is selected from one or more in the oxide of magnetic metal elemental iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, more preferably Fe 3o 4, Fe 2o 3, MnFe 2o 4, CoFe 2o 4, NiFe 2o 4, DyFe 2o 4or one or more in the oxide of holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium; Described oxide is preferably nanoparticle; More preferably, described nuclear magnetic resonance material is selected from one or both in ferroso-ferric oxide or iron sesquioxide, the preferred γ iron sesquioxide of described iron sesquioxide.
Further, described biocompatible materials is polyvinyl alcohol, and preferably, the mean molecule quantity of described polyvinyl alcohol is 1,000-500,000D, preferably 10,000-150,000D; Alcoholysis degree is 50-100%, preferably 75-100%;
Preferably, described embolism materials compositions is Polyvinyl Alcohol Embolization microcapsule, and the reactant feed of described Polyvinyl Alcohol Embolization microcapsule comprises: 1 weight account polyethylene alcohol, the roentgenopaque material of 0.5-7.5 weight portion, 0.2-5 weight portion nuclear magnetic resonance material, 1-5.5 weight portion inorganic salt, 4-15 weight portion cross-linking agent, 0.9-13.1 weight portion catalyst and 0-3 weight portion medicine;
Preferably, described embolism materials compositions is Polyvinyl Alcohol Embolization microcapsule, and described Polyvinyl Alcohol Embolization microcapsule reactant feed comprises: the not saturating X ray material of 1 weight account polyethylene alcohol, 1-6.5 weight portion, 0.7-4.5 weight portion nuclear magnetic resonance material, 2.5-3.5 weight portion inorganic salt, 6-11 weight portion cross-linking agent, 5.8-13.1 weight portion catalyst and 0.5-1.5 weight portion medicine;
Preferably, described embolism materials compositions is Polyvinyl Alcohol Embolization microsphere, and the reactant feed of described Polyvinyl Alcohol Embolization microsphere comprises: 1 weight account polyethylene alcohol, the roentgenopaque material of 2-8 weight portion and 0.5-4 weight portion nuclear magnetic resonance material, 0.015-0.31 weight portion inorganic salt, 0.6-2.3 weight portion cross-linking agent, 0.5-1.8 weight portion catalyst, 0.1-2.5 weight portion surfactant, 5-60 weight portion and the immiscible organic solvent of water and 0-6 weight portion medicine;
Preferably, described embolism materials compositions is Polyvinyl Alcohol Embolization microsphere, and the reactant feed of described Polyvinyl Alcohol Embolization microsphere comprises: 1 weight account polyethylene alcohol, the roentgenopaque material of 6-8 weight portion, 1-4 weight portion nuclear magnetic resonance material, 0.15-0.31 weight portion inorganic salt, 0.6-1.2 weight portion cross-linking agent, 0.8-1.5 weight portion catalyst, 0.6-2 weight portion surfactant, 10-50 weight portion and the immiscible organic solvent of water and 2-6 weight portion medicine.
Further, described biocompatible materials is gelatin; Preferably, described embolism materials compositions is gelatin embolism microcapsule, and the reactant feed of described gelatin embolism microcapsule comprises: 1 weight portion gelatin, the roentgenopaque material of 1-9.5 weight portion, 0.5-5 weight portion nuclear magnetic resonance material, 0.3-1.5 weight portion cross-linking agent and 0-4.5 weight portion medicine;
Preferably, described embolism materials compositions is gelatin embolism microcapsule, and the reactant feed of described gelatin embolism microcapsule comprises: 1 weight portion gelatin, the roentgenopaque material of 2-3.5 weight portion, 0.8-3 weight portion nuclear magnetic resonance material, 1.1-1.5 weight portion cross-linking agent and 0.5-4.5 weight portion medicine;
Preferably, described embolism materials compositions is gelatin embolism microsphere, and the reactant feed of described gelatin embolism microsphere comprises: 1 weight portion gelatin, the roentgenopaque material of 0.8-8 weight portion, 0.3-3.5 weight portion nuclear magnetic resonance material, 0.1-3.7 weight portion cross-linking agent, 0.1-3.13 weight portion surfactant, 5-50 weight portion and the immiscible organic solvent of water and 0-4.5 weight portion medicine;
Preferably, described embolism materials compositions is gelatin embolism microsphere, and the reactant feed of described gelatin embolism microsphere comprises: 1 weight portion gelatin, the roentgenopaque material of 0.8-2.2 weight portion, 0.5-3.5 weight portion nuclear magnetic resonance material, 0.7-3.7 weight portion cross-linking agent, 0.39-1.87 weight portion surfactant, 10-40 weight portion and the immiscible organic solvent of water and 0.5-4.5 weight portion medicine.
Further, described biocompatible materials is the mixture of chitosan and sodium carboxymethyl cellulose;
Described embolism materials compositions is chitosan-carboxymethyl cellulose thromboembolism microcapsule, and the reactant feed of described chitosan-carboxymethyl cellulose thromboembolism microcapsule comprises: 1 weight portion biocompatible materials, the roentgenopaque oily liquids of 4-10 weight portion and 0.5-5 weight portion nuclear magnetic resonance material, 0.2-0.8 weight portion cross-linking agent and 0-4.5 weight portion medicine.
Preferably, for the preparation of the inorganic salt of Polyvinyl Alcohol Embolization microsphere, be selected from one or more in water solublity sodium salt, potassium salt or ammonium salt; One or more in preferred potassium chloride, sodium chloride or ammonium chloride etc., more preferably sodium chloride; For the preparation of the inorganic salt of Polyvinyl Alcohol Embolization microcapsule, be selected from one or more in sulfate, phosphate, silicate or acetate, one or both in preferably sulfuric acid sodium, aluminum sulfate, ammonium sulfate, sodium tripolyphosphate etc., more preferably sodium sulfate;
Preferably, described cross-linking agent is selected from one or more in formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or hexandial etc.; Described catalyst is selected from one or more in hydrochloric acid, sulphuric acid, phosphoric acid, formic acid or acetic acid etc.;
Preferably, described surfactant be selected from spans surfactant or the mixture that formed by spans surfactant and Tweens surfactant in one or both, preferred one or both in sorbester p17 or sorbester p37;
Described embolism microball with the immiscible organic solvent of water in prepare, described and the immiscible organic solvent of water is selected from one or more in 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., preferred liquid paraffin or cyclohexane extraction;
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 (penicillin for example, oxacillin sodium, ampicillin, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid or sulbactam), tetracycline antibiotics (oxytetracycline for example, tetracycline or demeclocycline), aminoglycoside antibiotics (streptomycin, kanamycin A, gentamycin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribostamycin, bekanamycin, framycetin or paromomycin), macrolide antibiotics (erythromycin for example, Roxithromycin, clarithromycin or azithromycin) or other antibiotic (chloromycetin for example, ciclosporin or lincomycin) or its salt etc. in one or more.
Embolism materials compositions of the present invention can be kept in normal saline or phosphate buffer, or lyophilizing is preserved.
The using method of embolism materials compositions of the present invention is identical with the using method of common suppository.
The present invention further provides the preparation method of above-mentioned embolism materials compositions, described preparation method comprises the following steps:
Step a: biocompatible materials is mixed with to solution;
Step b: roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the solution of step a; Preferably, when roentgenopaque material is oily liquids, medicine and/or nuclear magnetic resonance material are dispersed in roentgenopaque material, obtain mixed liquor, then this mixed liquor is joined in the solution of step a;
Step c: adopt physical-chemical process, physical mechanical method or chemical method to make biocompatible materials generation polymerization, obtain embolism materials compositions.
Further, described embolism materials compositions is Polyvinyl Alcohol Embolization microcapsule, and described Polyvinyl Alcohol Embolization microcapsule adopts following methods preparation:
Step a1: take the polyvinyl alcohol of formula ratio, be mixed with 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, the more preferably poly-vinyl alcohol solution of 0.025g/ml;
Step b1: roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the poly-vinyl alcohol solution of step a1, stir, obtain mixed liquor;
Step c1: the inorganic salt that takes formula ratio, be mixed with 0.1-0.4g/ml, preferred 0.21-0.29g/ml, more preferably the inorganic salt solution of 0.25g/ml, the cloud point temperature of poly-vinyl alcohol solution under lower than this condition, preferably under the bath temperature of cloud point temperature 5-15 ℃ lower than poly-vinyl alcohol solution under this condition, inorganic salt solution is joined in the mixed liquor of step b1, continue to stir and slowly heat up, when temperature is increased to cloud point temperature, add cross-linking agent and catalyst, isothermal curing 15-23h, preferred consolidation 21-23h, more preferably solidify 22h, filter, after washing, obtain Polyvinyl Alcohol Embolization microcapsule, or,
Described Polyvinyl Alcohol Embolization microcapsule adopts following methods preparation:
Step a2: take the polyvinyl alcohol of formula ratio, be mixed with 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, the more preferably poly-vinyl alcohol solution of 0.025g/ml;
Step b2: the inorganic salt that takes formula ratio, be mixed with 0.1-0.4g/ml, preferred 0.21-0.29g/ml, more preferably the inorganic salt solution of 0.25g/ml, inorganic salt solution is mixed with the poly-vinyl alcohol solution in step a2, add subsequently roentgenopaque material, nuclear magnetic resonance material and optional medicine, the cloud point temperature of poly-vinyl alcohol solution under lower than this condition, preferably under the bath temperature of cloud point temperature 5-15 ℃ lower than poly-vinyl alcohol solution under this condition, stir, obtain mixed liquor;
Step c2: continue to stir also and slowly heat up, when temperature is increased to cloud point temperature, add cross-linking agent and catalyst, isothermal curing 15-23h, preferred consolidation 21-23h, more preferably solidifies 22h, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
Further, described embolism materials compositions is Polyvinyl Alcohol Embolization microsphere, and described Polyvinyl Alcohol Embolization microsphere adopts following methods preparation:
Step a3: the inorganic salt that takes formula ratio, be mixed with 0.0045-0.025g/ml, preferred 0.017-0.025g/ml, more preferably the inorganic salt solution of 0.02g/ml, the polyvinyl alcohol of formula ratio is dissolved in inorganic salt solution, obtaining polyvinyl alcohol concentration is 0.08-0.3g/ml, preferably 0.21-0.3g/ml, the more preferably solution of 0.21g/ml;
Step b3: under room temperature, roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the solution of step a3, stir, obtain mixed liquor;
Step c3: the mixed liquor impouring that step b3 is made containing surfactant with the immiscible organic solvent of water in, make Emulsion, add subsequently cross-linking agent and catalyst, under the mixing speed of 300-1500rpm and 30-65 ℃ of bath temperature, solidify 2-23h, preferably under the mixing speed of 550-650rpm and 30-45 ℃ of bath temperature, solidify 3.5-6h, more preferably under the mixing speed of 600rpm and 30 ℃ of bath temperatures, solidify 4h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing; Or in the mixed liquor of making at step b3, add cross-linking agent and catalyst, after stirring impouring containing surfactant with the immiscible organic solvent of water in, make Emulsion, then under the mixing speed of 300-1500rpm and 30-65 ℃ of bath temperature, solidify 2-23h, preferably under the mixing speed of 550-650rpm and 30-45 ℃ of bath temperature, solidify 3.5-6h, more preferably under the mixing speed of 600rpm and 30 ℃ of bath temperatures, solidify 4h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing.
Further, described embolism materials compositions is gelatin embolism microcapsule or gelatin embolism microsphere; Described gelatin embolism microcapsule adopts following methods preparation:
Step a4: take the gelatin of formula ratio, by gelatin with making 0.005-0.1g/ml after distilled water swelling, preferably 0.005-0.035g/ml, the more preferably gelatin solution of 0.035g/ml;
Step b4:, roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the gelatin solution of step a4 preferably under 53 ℃ of water bath condition at 40-60 ℃, stir, obtain mixed liquor; Then regulate the pH value of mixed liquor to 3.5-4.1, preferably drip 0.1g/ml acetum and regulate the pH value of mixed liquor to 3.5-4.1, after microcapsule forms, add distilled water diluting, obtain microcapsule suspension;
Step c4: the microcapsule suspension that step b4 is obtained adds cross-linking agent to solidify 0.5-24h under ice-water bath condition, preferably 70min or 15h, obtain gelatin embolism microcapsule after filtering, washing;
When cross-linking agent is formaldehyde, above-mentioned steps c4 specifically comprises: the microcapsule suspension that step b4 is obtained adds formaldehyde to stir 2-15min under ice-water bath condition, preferred 10min, regulate pH value to 8-9, preferably dripping 0.1g/ml sodium hydroxide solution regulates pH value to 8-9, solidify 0.5-24h, preferably 15h, obtains gelatin embolism microcapsule after filtering, washing.
Described gelatin embolism microsphere adopts following methods preparation:
Step a5: take the gelatin of formula ratio, by gelatin with making 0.08-0.35g/ml after distilled water swelling, preferably 0.15-0.30g/ml, the more preferably gelatin solution of 0.28g/ml;
Step b5:, roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the gelatin solution of step a5 preferably under 53 ℃ of water bath condition at 35-63 ℃, stir, obtain mixed liquor;
Step c5: the mixed liquor impouring that step b5 is made containing surfactant with the immiscible organic solvent of water in, make Emulsion, Emulsion is transferred to and in ice-water bath, stirred 5-60min, preferred 30min, add cross-linking agent, solidify 0.5-24h, preferably 70min or 15h, obtain gelatin embolism microsphere after filtering, washing.
When cross-linking agent is formaldehyde, above-mentioned steps c5 specifically comprises: the mixed liquor impouring that step b5 is made containing surfactant with the immiscible organic solvent of water in, make Emulsion, Emulsion is transferred to and in ice-water bath, is stirred 5-60min, preferred 30min, add formaldehyde to stir 2-15min, preferably 10min, regulates pH value to 8-9, preferably dripping 0.1g/ml sodium hydroxide solution regulates pH value to 8-9, solidify 0.5-24h, preferably 15h, obtains gelatin embolism microsphere after filtering, washing.
Further, described embolism materials compositions is chitosan-carboxymethyl cellulose thromboembolism microcapsule, and described chitosan-carboxymethyl cellulose thromboembolism sodium microcapsule adopts following methods preparation:
Step a6: the chitosan that takes formula ratio, preparation is containing the acetum of 0.006-0.009g/ml chitosan, take the sodium carboxymethyl cellulose of formula ratio, the sodium carboxymethyl cellulose solution of preparation 0.02-0.056g/ml, is mixed to get mixed solution by the acetum of chitosan and sodium carboxymethyl cellulose solution;
Step b6: roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the mixed solution of step a6, stir, make mixed liquor, regulate the pH value of mixed liquor to 5.5-6.5, preferably with 0.1g/ml sodium hydroxide solution, regulate the pH value of Emulsion to 5.5-6.5, reaction 5-60min, preferably 20min;
Step c6: the reactant liquor in step b6 is placed in to ice-water bath, adds cross-linking agent, the preferred 1h of crosslinking curing 0.5-2h, obtains chitosan-carboxymethyl cellulose thromboembolism microcapsule after filtering, washing.
The present invention further provides above-mentioned embolism materials compositions for the preparation for the treatment of tumor, for example 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 of the medicine that stops blooding etc.
Compared with prior art, embolism materials compositions of the present invention at least has the following advantages:
1, the present invention is by adopting biocompatible materials to wrap up the embolism materials compositions that roentgenopaque material and the preparation of nuclear magnetic resonance material have X ray and the two imaging capabilities of magnetic resonance, make embolism materials compositions there is good biocompatibility, and can be simultaneously by X ray image equipment and MRI direct-detection.Compare with the suppository that simple X ray or MRI develop, embolism materials compositions of the present invention is not limited to uses single equipment monitoring, can monitor according to any X ray image equipment (as CT, DSA) or MRI of selecting that self need of the appointed condition of hospital and patient, be convenient in Embolization and postoperative inspection effect of embolization, more convenient use.
2, compare with nonvisualized suppository, embolism materials compositions of the present invention is convenient to doctor in Embolization and monitoring after operation suppository present position and thromboembolism terminal, has improved effect and the safety for the treatment of.
3, can in embolism materials compositions of the present invention, be written into medicine, and medicine carrying embolism materials compositions thromboembolism under X ray image equipment (as CT) or MRI monitoring, to specific part, can have been realized to the targeted delivery of contained medicine better; And can realize the slow release of medicine from microgranule, and in thromboembolism part, maintain for a long time higher drug level, compare with perfusion therapy, can reduce the whole body toxic and side effects of medicine, be conducive to improve the curative effect of embolotherapy.
4, the present invention adopts biocompatible materials, roentgenopaque material and nuclear magnetic resonance material to prepare embolism materials compositions, and preparation technology is simple, and cost is low, is applicable to large-scale industrial production.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is the optical microscope photograph of the Polyvinyl Alcohol Embolization microsphere of the embodiment of the present invention 5 preparations;
Fig. 2 is the external CT detected image of the Polyvinyl Alcohol Embolization microsphere of the embodiment of the present invention 5 preparations;
Fig. 3 is the external MRI detected image of the Polyvinyl Alcohol Embolization microsphere of the embodiment of the present invention 5 preparations;
Fig. 4 is that the Polyvinyl Alcohol Embolization microsphere of the embodiment of the present invention 5 preparation is at the subcutaneous CT image of mice;
Fig. 5 is that the Polyvinyl Alcohol Embolization microsphere of the embodiment of the present invention 5 preparation is at the subcutaneous MRI image of mice;
Fig. 6 is the tablets in vitro curve that carries paclitaxel Polyvinyl Alcohol Embolization microsphere of the embodiment of the present invention 8 preparations.
The specific embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is conventional method.In following embodiment, medicine material used, reagent, material etc., if no special instructions, be commercially available purchase product.
embodiment 1the preparation of Polyvinyl Alcohol Embolization microcapsule
1) take 1g polyvinyl alcohol, be mixed with the poly-vinyl alcohol solution of 0.008g/ml;
2) by joining after 6.5g iodized oil, 5g ferriferrous oxide nano-particle and 1.5g paclitaxel mix homogeneously in the poly-vinyl alcohol solution that step 1) obtains, stir and make oil-in-water (o/w) type Emulsion;
3) take 3.0g sodium sulfate, be mixed with the metabisulfite solution of 0.21g/ml, under lower than this condition, under the bath temperature of the cloud point temperature 5-15 of poly-vinyl alcohol solution ℃, metabisulfite solution is joined to step 2) in the Emulsion that obtains, continue to stir and slowly heat up, when temperature is increased to cloud point temperature, add 11g formaldehyde and 5.8g sulphuric acid, isothermal curing 20h, stratification, inclines and supernatant, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
embodiment 2the preparation of Polyvinyl Alcohol Embolization microsphere
1) take 0.31g sodium chloride, the sodium-chloride water solution of preparation 0.025g/ml, is dissolved in 1g polyvinyl alcohol in sodium-chloride water solution, obtains the solution that polyvinyl alcohol concentration is 0.08g/ml;
2) 2g ferric oxide nanoparticles and 6g paclitaxel are dispersed in 8g iodized oil, obtain mixed liquor, then at room temperature this mixed liquor is joined to the poly-vinyl alcohol solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) by step 2) the Emulsion impouring of making is containing in the 60g liquid paraffin of 2.5g sorbester p37, make Water-In-Oil oil-in (o/w/o) emulsion, add subsequently 0.6g glutaraldehyde and 0.5g sulphuric acid, under the mixing speed of 300rpm and 35 ℃ of bath temperatures, solidify 2h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing.
embodiment 3the preparation of gelatin embolism microcapsule
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.03g/ml after distilled water swelling;
2) 0.5g Sorafenib and 3g ferroso-ferric oxide are dispersed in 3.5g iodized oil, obtain mixed liquor, under 40 ℃ of water bath condition, the mixed liquor obtaining is joined in the gelatin solution of step 1), stir, make oil-in-water (o/w) type Emulsion, then dripping 0.1g/ml acetum regulates the pH value of Emulsion to 3.5-4.1, after examining under a microscope microcapsule and forming, add distilled water diluting, obtain microcapsule suspension;
3) by step 2) the microcapsule suspension that obtains adds 1.5g formaldehyde to stir 2min under ice-water bath condition, drips 0.1g/ml sodium hydroxide solution, regulates pH value to 8-9, solidifies 15h, and stratification, inclines and supernatant, filters, obtains gelatin embolism microcapsule after washing.
embodiment 4the preparation of Polyvinyl Alcohol Embolization microsphere
1) take 0.15g sodium chloride, the sodium-chloride water solution of preparation 0.018g/ml, is dissolved in 1g polyvinyl alcohol in sodium-chloride water solution, the solution that preparation polyvinyl alcohol concentration is 0.12g/ml;
2) 4g ferric oxide nanoparticles and 1.5g Sorafenib are dispersed in 6g iofendylate, obtain mixed liquor, then at room temperature this mixed liquor is joined in the poly-vinyl alcohol solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) by step 2) the Emulsion impouring of making is containing in the 17g Oleum Ricini of 0.4g sorbester p37, make Water-In-Oil bag oil (o/w/o) type emulsion, add subsequently 0.8g formaldehyde and 0.6g sulphuric acid, under the mixing speed of 1500rpm and 45 ℃ of bath temperatures, solidify 7h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing.
embodiment 5the preparation of Polyvinyl Alcohol Embolization microsphere
1) take 0.17g sodium chloride, the sodium-chloride water solution of preparation 0.025g/ml, is dissolved in 1g polyvinyl alcohol in sodium-chloride water solution, obtains the solution that polyvinyl alcohol concentration is 0.15g/ml;
2) under room temperature, will after 7g iodized oil, 1.7g ferriferrous oxide nano-particle mix homogeneously, join in the poly-vinyl alcohol solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) in step 2) add 0.9g formaldehyde and 0.8g sulphuric acid in the Emulsion made, after stirring rapidly, impouring is containing in the 50g liquid paraffin of 2g sorbester p17, make Water-In-Oil bag oil (o/w/o) type emulsion, under the mixing speed of 750rpm and 30 ℃ of bath temperatures, solidify 4h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing.
The form of the Polyvinyl Alcohol Embolization microsphere of above-mentioned preparation under optical microscope as shown in Figure 1.As can be seen from Figure 1, the Polyvinyl Alcohol Embolization microsphere of preparation is the spherical of rule, and dispersibility is better, without bonding and agglomeration.
embodiment 6the preparation of gelatin embolism microsphere
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.3g/ml after distilled water swelling;
2) under 53 ℃ of water bath condition, by 0.5g MnFe 2o 4be dispersed in 1.2g iodized oil and make mixed liquor, mixed liquor is joined in the gelatin solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) by step 2) the Emulsion impouring of making is containing in the 10g cyclohexane extraction of 0.39g sorbester p17, make Water-In-Oil bag oil (o/w/o) type Emulsion, Emulsion is transferred to continuation in ice-water bath and stir 30min, add 0.2g formaldehyde to stir 2min, drip 0.1g/ml sodium hydroxide solution, regulate pH value to 8-9, solidify 10h, stratification, inclines and supernatant, after filtering, washing, obtains gelatin embolism microsphere.
embodiment 7the preparation of chitosan-carboxymethyl cellulose thromboembolism microcapsule
1) take 0.1g chitosan, make the acetum containing 0.006g/ml chitosan, take 0.9g sodium carboxymethyl cellulose, make the sodium carboxymethyl cellulose solution of 0.056g/ml, the acetum of chitosan and sodium carboxymethyl cellulose solution are mixed to get to mixed solution;
2) will after 4g iodized oil and 0.5g ferric oxide nanoparticles mix homogeneously, join in the mixed solution of step 1), magnetic agitation is made oil-in-water (o/w) type Emulsion; With 0.1g/ml sodium hydroxide solution, regulate the pH value of Emulsion to 5.5-6.5, reaction 5min;
3) by step 2) in reactant liquor be placed in ice-water bath, add 0.2g glutaraldehyde, crosslinking curing 0.5h, stratification, inclines and supernatant, filters, obtains chitosan-carboxymethyl cellulose thromboembolism microcapsule after washing.
embodiment 8the preparation of Polyvinyl Alcohol Embolization microsphere
1) take 0.015g sodium chloride, the sodium-chloride water solution of preparation 0.0045g/ml, is dissolved in 1g polyvinyl alcohol in sodium-chloride water solution, obtains the solution that polyvinyl alcohol concentration is 0.3g/ml;
2) under room temperature, 1.2g paclitaxel, 0.8g ferriferrous oxide nano-particle are dispersed in 2.2g iodized oil and make mixed liquor, mixed liquor is joined in the poly-vinyl alcohol solution of step 1), make oil-in-water (o/w) type Emulsion;
3) in step 2) add 2.3g glutaraldehyde and 1.8g sulphuric acid in the Emulsion made, after mix homogeneously, impouring, containing in the 5g liquid paraffin of 0.1g sorbester p37, is solidified 16h under 550rpm and 55 ℃ of bath temperatures, filters, obtains Polyvinyl Alcohol Embolization microsphere after washing.
embodiment 9the preparation of gelatin embolism microcapsule
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.1g/ml after distilled water swelling;
2) under 50 ℃ of water bath condition, 0.8g γ iron sesquioxide is dispersed in 1g iodized oil, make mixed liquor, mixed liquor is joined in the gelatin solution of step 1), stir, make oil-in-water (o/w) type Emulsion; Then drip 0.1g/ml acetum and regulate the pH value of Emulsion to 3.5-4.1, after examining under a microscope microcapsule and forming, add distilled water diluting, obtain microcapsule suspension;
3) by step 2) the microcapsule suspension that obtains adds 0.3g glutaraldehyde to solidify 70min under ice-water bath condition, and stratification, inclines and supernatant, filters, obtains gelatin embolism microcapsule after washing.
embodiment 10the preparation of Polyvinyl Alcohol Embolization microcapsule
1) take 1g polyvinyl alcohol, be mixed with the poly-vinyl alcohol solution of 0.0035g/ml;
2) by joining after 7g iodized oil, 0.5g tantalum powder, 4.5g ferriferrous oxide nano-particle and 3g paclitaxel mix homogeneously in the poly-vinyl alcohol solution that step 1) obtains, stir and make oil-in-water (o/w) type Emulsion;
3) take 5.5g sodium sulfate, be mixed with the metabisulfite solution of 0.1g/ml, under lower than this condition, under the bath temperature of the cloud point temperature 5-15 of poly-vinyl alcohol solution ℃, metabisulfite solution is joined to step 2) in the Emulsion that obtains, continue to stir and slowly heat up, when temperature is increased to cloud point temperature, add 15g formaldehyde and 13.1g sulphuric acid, isothermal curing 23h, stratification, inclines and supernatant, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
embodiment 11the preparation of Polyvinyl Alcohol Embolization microcapsule
1) take 1g polyvinyl alcohol, be mixed with the poly-vinyl alcohol solution of 0.025g/ml;
2) take 2.5g sodium sulfate, be mixed with the metabisulfite solution of 0.29g/ml, metabisulfite solution is mixed with the poly-vinyl alcohol solution in step 1), the 2.1g iodized oil and the 1.7g ferriferrous oxide nano-particle that add subsequently mix homogeneously, under the bath temperature of cloud point temperature 5-15 ℃ of poly-vinyl alcohol solution, stir under lower than this condition, obtain oil-in-water type (o/w) Emulsion;
3) continue stirring and slowly heat up, when temperature is increased to cloud point temperature, adding 8g formaldehyde and 1.8g hydrochloric acid, isothermal curing 23h, stratification, inclines and supernatant, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
embodiment 12the preparation of Polyvinyl Alcohol Embolization microcapsule
1) take 1g polyvinyl alcohol, be mixed with the poly-vinyl alcohol solution of 0.015g/ml;
2) take 3.5g sodium sulfate, be mixed with the metabisulfite solution of 0.262g/ml, metabisulfite solution is mixed with the poly-vinyl alcohol solution in step 1), the 3.5g iodized oil, 2.4g ferriferrous oxide nano-particle and the 1.1g amycin that add subsequently mix homogeneously, under the bath temperature of cloud point temperature 5-15 ℃ of poly-vinyl alcohol solution, stir under lower than this condition, obtain oil-in-water type (o/w) Emulsion;
3) continue stirring and slowly heat up, when temperature is increased to cloud point temperature, adding 10g formaldehyde and 11g hydrochloric acid, isothermal curing 20h, stratification, inclines and supernatant, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
embodiment 13the preparation of Polyvinyl Alcohol Embolization microcapsule
1) take 1g polyvinyl alcohol, be mixed with the poly-vinyl alcohol solution of 0.05g/ml;
2) 0.2g ferriferrous oxide nano-particle is dispersed in 0.5g iodized oil, obtains mixed liquor, then mixed liquor is joined in the poly-vinyl alcohol solution that step 1) obtains, stir and make oil-in-water (o/w) type Emulsion;
3) take 1g sodium tripolyphosphate, be mixed with the sodium tripolyphosphate solution of 0.25g/ml, under lower than this condition, under the bath temperature of the cloud point temperature 5-15 of poly-vinyl alcohol solution ℃, sodium tripolyphosphate solution is joined to step 2) in the Emulsion that obtains, continue to stir and slowly heat up, when temperature is increased to cloud point temperature, add 4g formaldehyde and 0.9g sulphuric acid, isothermal curing 15h, stratification, inclines and supernatant, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
embodiment 14the preparation of Polyvinyl Alcohol Embolization microsphere
1) take 0.043g sodium chloride, the sodium-chloride water solution of preparation 0.01g/ml, is dissolved in 1g polyvinyl alcohol in sodium-chloride water solution, obtains the solution that polyvinyl alcohol concentration is 0.23g/ml;
2) at room temperature will after 2.8g iodized oil, 1.2g ferriferrous oxide nano-particle and 1.5g paclitaxel mix homogeneously, join in the poly-vinyl alcohol solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) in step 2) add 1.2g glutaraldehyde and 1.1g sulphuric acid in the Emulsion made, after mix homogeneously, impouring, containing in the 11g liquid paraffin of 0.4g sorbester p37, is solidified 23h under 600rpm and 65 ℃ of bath temperatures, filters, obtains Polyvinyl Alcohol Embolization microsphere after washing.
embodiment 15the preparation of gelatin embolism microcapsule
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.035g/ml after distilled water swelling;
2) under 60 ℃ of water bath condition, to after 1.5g iodized oil, 0.5g tantalum powder, 0.5g ferriferrous oxide nano-particle and 0.5g Sorafenib mix homogeneously, join in the gelatin solution of step 1), stir, make mixed liquor, then dripping 0.1g/ml acetum regulates the pH value of Emulsion to 3.5-4.1, after examining under a microscope microcapsule and forming, add distilled water diluting, obtain microcapsule suspension;
3) by step 2) the microcapsule suspension that obtains adds 0.1g formaldehyde to stir 15min under ice-water bath condition, drips 0.1g/ml sodium hydroxide solution, regulates pH value to 8-9, solidify 10h, stratification, inclines and supernatant, after filtering, washing, obtains gelatin embolism microcapsule.
embodiment 16the preparation of gelatin embolism microsphere
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.28g/ml after distilled water swelling;
2) under 45 ℃ of water bath condition, will after 2g iodized oil, 0.2g tantalum powder, 1g ferriferrous oxide nano-particle and 1g paclitaxel mix homogeneously, join in the gelatin solution of step 1), stir, make mixed liquor;
3) by step 2) the Emulsion impouring of making is containing in the 25g liquid paraffin of 0.51g sorbester p17, make oil-in-water (w/o) type Emulsion, Emulsion is transferred to continuation in ice-water bath and stir 5min, add 0.7g glutaraldehyde to solidify 70min, stratification, incline and supernatant, after filtering, washing, obtain gelatin embolism microsphere.
embodiment 17the preparation of gelatin embolism microsphere
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.08g/ml after distilled water swelling;
2) under 63 ℃ of water bath condition, will after 8g iodized oil, 3.5g ferriferrous oxide nano-particle and 4.5g paclitaxel mix homogeneously, join in the gelatin solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) by step 2) the Emulsion impouring of making is containing in the 50g liquid paraffin of 3.13g sorbester p17, make Water-In-Oil bag oil (o/w/o) type Emulsion, Emulsion is transferred to continuation in ice-water bath and stir 60min, add 3.7g formaldehyde to stir 10min, drip 0.1g/ml sodium hydroxide solution, regulate pH value to 8-9, solidify 15h, stratification, inclines and supernatant, after filtering, washing, obtains gelatin embolism microsphere.
embodiment 18the preparation of gelatin embolism microsphere
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.35g/ml after distilled water swelling;
2) under 35 ℃ of water bath condition, by 0.8g iodized oil, 0.3g DyFe 2o 4after nanoparticle and 0.5g Sorafenib mix homogeneously, join in the gelatin solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) by step 2) the Emulsion impouring of making is containing in the 5g liquid paraffin of 0.1g sorbester p17, make Water-In-Oil bag oil (o/w/o) type Emulsion, Emulsion is transferred to continuation in ice-water bath and stir 20min, add 0.1g formaldehyde to stir 15min, drip 0.1g/ml sodium hydroxide solution, regulate pH value to 8-9, solidify 24h, stratification, inclines and supernatant, after filtering, washing, obtains gelatin embolism microsphere.
embodiment 19the preparation of chitosan-carboxymethyl cellulose thromboembolism microcapsule
1) take 0.5g chitosan, make the acetum containing 0.009g/ml chitosan, take 0.5g sodium carboxymethyl cellulose, make the sodium carboxymethyl cellulose solution of 0.035g/ml, the acetum of chitosan and sodium carboxymethyl cellulose solution are mixed to get to mixed solution;
2) will after 5g iodized oil, 2.5g ferric oxide nanoparticles and 2.4g cisplatin mix homogeneously, join in the mixed solution of step 1), magnetic agitation is made oil-in-water (o/w) type Emulsion; With 0.1g/ml sodium hydroxide solution, regulate the pH value of Emulsion to 5.5-6.5, reaction 20min;
3) by step 2) in reactant liquor be placed in ice-water bath, add 0.8g glutaraldehyde, crosslinking curing 2h, stratification, inclines and supernatant, filters, obtains chitosan-carboxymethyl cellulose thromboembolism microcapsule after washing.
embodiment 20the preparation of Polyvinyl Alcohol Embolization microcapsule
1) take 1g polyvinyl alcohol, be mixed with the poly-vinyl alcohol solution of 0.04g/ml;
2) by joining after 1g iodized oil, 0.7g ferriferrous oxide nano-particle and 0.2g Docetaxel mix homogeneously in the poly-vinyl alcohol solution that step 1) obtains, stir and make oil-in-water (o/w) type Emulsion;
3) take 2g aluminum sulfate, be mixed with the aluminum sulfate solution of 0.4g/ml, under lower than this condition, under the bath temperature of the cloud point temperature 5-15 of poly-vinyl alcohol solution ℃, aluminum sulfate solution is joined to step 2) in the Emulsion that obtains, continue to stir and slowly heat up, when temperature is increased to cloud point temperature, add 6g formaldehyde and 9.5g sulphuric acid, isothermal curing 21h, stratification, inclines and supernatant, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
embodiment 21the preparation of Polyvinyl Alcohol Embolization microcapsule
1) take 1g polyvinyl alcohol, be mixed with the poly-vinyl alcohol solution of 0.035g/ml;
2) by joining after 1.5g iodized oil, 1g ferriferrous oxide nano-particle and 0.5g Sorafenib mix homogeneously in the poly-vinyl alcohol solution that step 1) obtains, stir and make oil-in-water (o/w) type Emulsion;
3) take 1g ammonium sulfate, be mixed with the ammonium sulfate of 0.175g/ml, under lower than this condition, under the bath temperature of the cloud point temperature 5-15 of poly-vinyl alcohol solution ℃, ammonium sulfate is joined to step 2) in the Emulsion that obtains, continue to stir and slowly heat up, when temperature is increased to cloud point temperature, add 8g formaldehyde and 3.1g sulphuric acid, isothermal curing 22h, stratification, inclines and supernatant, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
embodiment 22the preparation of Polyvinyl Alcohol Embolization microsphere
1) take 0.081g sodium chloride, the sodium-chloride water solution of preparation 0.017g/ml, is dissolved in 1g polyvinyl alcohol in sodium-chloride water solution, obtains the solution that polyvinyl alcohol concentration is 0.21g/ml;
2) at room temperature will after 3g iodized oil, 1g ferric oxide nanoparticles and 2g paclitaxel mix homogeneously, join in the poly-vinyl alcohol solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) by step 2) the Emulsion impouring of making is containing in the 14g cyclohexane extraction of 0.6g sorbester p37, make Water-In-Oil oil-in (o/w/o) emulsion, add subsequently 1.1g glutaraldehyde and 0.9g sulphuric acid, under the mixing speed of 650rpm and 40 ℃ of bath temperatures, solidify 6h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing.
embodiment 23the preparation of Polyvinyl Alcohol Embolization microsphere
1) take 0.074g sodium chloride, the sodium-chloride water solution of preparation 0.02g/ml, is dissolved in 1g polyvinyl alcohol in sodium-chloride water solution, obtains the solution that polyvinyl alcohol concentration is 0.27g/ml;
2) at room temperature will after 2g iodized oil, 0.5g ferric oxide nanoparticles and 1g paclitaxel mix homogeneously, join in the poly-vinyl alcohol solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) by step 2) the Emulsion impouring of making is containing in the 10g liquid paraffin of 0.7g sorbester p37, make Water-In-Oil oil-in (o/w/o) emulsion, add subsequently 1.4g glutaraldehyde and 1.5g sulphuric acid, under the mixing speed of 900rpm and 45 ℃ of bath temperatures, solidify 3.5h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing.
embodiment 24the preparation of gelatin embolism microcapsule
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.025g/ml after distilled water swelling;
2) under 46 ℃ of water bath condition, to after 2.5g iodized oil, 1g ferriferrous oxide nano-particle and 1.5g Sorafenib mix homogeneously, join in the gelatin solution of step 1), stir, make oil-in-water (o/w) type Emulsion, then dripping 0.1g/ml acetum regulates the pH value of Emulsion to 3.5-4.1, after examining under a microscope microcapsule and forming, add distilled water diluting, obtain microcapsule suspension;
3) by step 2) the microcapsule suspension that obtains adds 1.1g formaldehyde to stir 10min under ice-water bath condition, drips 0.1g/ml sodium hydroxide solution, regulates pH value to 8-9, solidify 24h, stratification, inclines and supernatant, after filtering, washing, obtains gelatin embolism microcapsule.
embodiment 25the preparation of gelatin embolism microcapsule
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.005g/ml after distilled water swelling;
2) under 53 ℃ of water bath condition, to after 9.5g iodized oil, 5g ferriferrous oxide nano-particle and 4.5g Sorafenib mix homogeneously, join in the gelatin solution of step 1), stir, make oil-in-water (o/w) type Emulsion, then dripping 0.1g/ml acetum regulates the pH value of Emulsion to 3.5-4.1, after examining under a microscope microcapsule and forming, add distilled water diluting, obtain microcapsule suspension;
3) by step 2) the microcapsule suspension that obtains adds 1.3g glutaraldehyde to solidify 0.5h under ice-water bath condition, and stratification, inclines and supernatant, filters, obtains gelatin embolism microcapsule after washing.
embodiment 26the preparation of gelatin embolism microsphere
1) take 1g gelatin, by gelatin with making the gelatin solution of 0.15g/ml after distilled water swelling;
2) under 60 ℃ of water bath condition, will after the 1.6g iodized oil of mix homogeneously, 0.7g ferriferrous oxide nano-particle and 0.7g Sorafenib mix homogeneously, join in the gelatin solution of step 1), stir, make oil-in-water (o/w) type Emulsion;
3) by step 2) the Emulsion impouring of making is containing in the 40g liquid paraffin of 1.87g sorbester p17, make Water-In-Oil bag oil (o/w/o) type Emulsion, Emulsion is transferred to continuation in ice-water bath and stir 10min, add 2g glutaraldehyde, solidify 0.5h, stratification, inclines and supernatant, after filtering, washing, obtains gelatin embolism microsphere.
embodiment 27the preparation of chitosan-carboxymethyl cellulose thromboembolism microcapsule
1) take 0.4g chitosan, make the acetum containing 0.007g/ml chitosan, take 0.6g sodium carboxymethyl cellulose, make the sodium carboxymethyl cellulose solution of 0.02g/ml, the acetum of chitosan and sodium carboxymethyl cellulose solution are mixed to get to mixed solution;
2) will after the 10g iodized oil of mix homogeneously, 5g ferric oxide nanoparticles and 4.5g paclitaxel mix homogeneously, join in the mixed solution of step 1), magnetic agitation is made oil-in-water (o/w) type Emulsion; With 0.1g/ml sodium hydroxide solution, regulate the pH value of Emulsion to 5.5-6.5, reaction 60min;
3) by step 2) in reactant liquor be placed in ice-water bath, add 0.5g glutaraldehyde, crosslinking curing 1h, stratification, inclines and supernatant, filters, obtains chitosan-carboxymethyl cellulose thromboembolism microcapsule after washing.
comparative examplethe preparation of blank Polyvinyl Alcohol Embolization microsphere
Except not adding iodized oil and ferriferrous oxide nano-particle, each constituent content and preparation technology are all identical with embodiment 5, and concrete preparation method is as follows:
1) take 0.17g sodium chloride, the sodium-chloride water solution of preparation 0.025g/ml, is dissolved in 1g polyvinyl alcohol in sodium-chloride water solution, the solution that preparation polyvinyl alcohol concentration is 0.15g/ml;
2) in the poly-vinyl alcohol solution of step 1), add 0.9g formaldehyde and 0.8g sulphuric acid, mix homogeneously, obtains mixed solution; Mixed solution impouring, containing in the 50g liquid paraffin of 2g sorbester p17, is made to water-in-oil type (w/o) Emulsion, under the mixing speed of 750rpm and 30 ℃ of bath temperatures, solidify 4h, filter, after washing, obtain blank polyvinyl alcohol microparticles.
test 1the external CT of embolism microball and MRI detect
Blank Polyvinyl Alcohol Embolization microsphere prepared by the Polyvinyl Alcohol Embolization microsphere of respectively being prepared by embodiment 5 and comparative example carries out external CT and MRI detects.Experimentation is as follows: prepare 2% agar hot solution, in impouring culture dish, making liquid level thickness is 1.5cm, after the cooling formation gel of solution, Polyvinyl Alcohol Embolization microsphere and blank Polyvinyl Alcohol Embolization microsphere are placed on respectively to agar surface, also cooling in the agar hot solution that impouring thickness is 1cm again, then surface plate is placed in respectively under CT and 3T MRI and is scanned, testing result under CT and 3T MRI is respectively as shown in Figures 2 and 3: (number of both sides microsphere is respectively 1 from top to bottom in Fig. 2 and Fig. 3, to show respectively the external CT of Polyvinyl Alcohol Embolization microsphere (right side) and blank Polyvinyl Alcohol Embolization microsphere (left side) and 3T MRI testing result, 2, 3, 4, 5), from Fig. 2 and Fig. 3, find out, under CT and 3T MRI, polyvinyl alcohol magnetic microsphere is high-visible, and blank Polyvinyl Alcohol Embolization microsphere is not detected substantially.
test 2embolism microball detects at the subcutaneous CT of mice and MRI
From the Polyvinyl Alcohol Embolization microsphere of embodiment 5 preparation, sieve out the microsphere of 100-300 μ m, by 2.5ml microsphere suspendible to 20ml containing in the normal saline of 1% sodium carboxymethyl cellulose, getting 0.15ml, to inject mice subcutaneous.Mice is placed under CT and 3T MRI and is scanned, and the testing result under CT and 3T MRI respectively as shown in Figure 4 and Figure 5.Fig. 4 shows Polyvinyl Alcohol Embolization microsphere at the subcutaneous CT image of mice, and white arrow indicates injection site.Fig. 5 shows Polyvinyl Alcohol Embolization microsphere at the subcutaneous MRI image of mice, the external white bright spot of Fig. 5 small mouse is vitamin E capsule, white arrow indicates injection site, and CT and MRI result show, at mouse subcutaneous injection position, all can detect Polyvinyl Alcohol Embolization microsphere.
test 3thromboembolism in embolism microball body
The Polyvinyl Alcohol Embolization microsphere making from embodiment 5, sieve out the microsphere that particle diameter is 100-150 μ m, standby after sterilizing.To after family's rabbit anesthesia of fasting 12h, be fixed on operating-table, a separated bilateral common carotid artery, under digital subtraction angiography (DSA), through carotid artery, with 2.8F conduit and seal wire, carry out selectivity left renal artery intubate, inject 0.15ml microsphere and carry out renal infarction, before and after thromboembolism, all left kidney is carried out to DSA inspection whether inaccessible to determine target vessel.Postoperative CT and the MRI of carrying out detects, and the testing result of CT and MRI all shows that the position at microsphere place is consistent with DSA check result.
test 4the release experiment of medicine carrying embolism microball
Adopt T shape pipe method to measure the release in vitro of carrying paclitaxel Polyvinyl Alcohol Embolization microsphere of embodiment 8 preparations.Experimentation is as follows: in T-shaped pipe, add the phosphate buffer of 200ml pH7.4 as release medium, buffer mobility is 50ml/min, and bath temperature is 37 ℃.The above-mentioned microsphere of 1ml is placed in to the bottom of T shape pipe, in 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, take out respectively 5ml release medium and supply immediately isothermal, isopyknic fresh release medium, under 227nm wavelength, measuring absorbance, according to standard curve, calculating release amount.Carry the release curve of paclitaxel Polyvinyl Alcohol Embolization microsphere as shown in Figure 6.As can be seen from Figure 6, carry paclitaxel Polyvinyl Alcohol Embolization microsphere very fast at front 4h rate of releasing drug, during 4h, cumulative release approximately 45%, and during 24h, cumulative release approximately 61%.
Specific description of embodiments of the present invention above does not limit the present invention, and those skilled in the art can make according to the present invention various changes or distortion, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.

Claims (14)

1. an embolism materials compositions, it is made by reactant feed, described reactant feed comprises: biocompatible materials, roentgenopaque material and nuclear magnetic resonance material, in described embolism materials compositions, roentgenopaque material and nuclear magnetic resonance material are wrapped up by biocompatible materials.
2. embolism materials compositions according to claim 1, it is characterized in that, described reactant feed comprises: 1 weight portion biocompatible materials, the roentgenopaque material of 0.5-10 weight portion, 0.2-5 weight portion nuclear magnetic resonance material and 0-6 weight portion medicine; Wherein, described medicine is wrapped up by biocompatible materials.
3. embolism materials compositions according to claim 1 and 2, is characterized in that, described embolism materials compositions is spherical or erose microgranule, preferably microcapsule or microsphere;
Preferably, the particle diameter of described microgranule is 10-2000 μ m.
4. according to the embolism materials compositions described in any one in claims 1 to 3, it is characterized in that, described biocompatible materials be selected from polyvinyl alcohol, alginic acid, alginate, chitosan, gelatin, arabic gum, starch, starch derivatives, cellulose, cellulose derivative, polylactic acid or the copolymer that formed by lactic acid and hydroxyacetic acid in one or more;
Preferably, described roentgenopaque material is selected from one or both in roentgenopaque oily liquids or roentgenopaque solid, preferred roentgenopaque oily liquids, more preferably one or both in iodized oil or iofendylate; Described roentgenopaque solid is selected from one or both in tantalum powder or barium sulfate;
Preferably, described nuclear magnetic resonance material is selected from one or more in the compound of magnetic metal elemental iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium; Preferably, described nuclear magnetic resonance material is selected from one or more in the oxide of magnetic metal elemental iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, more preferably Fe 3o 4, Fe 2o 3, MnFe 2o 4, CoFe 2o 4, NiFe 2o 4, DyFe 2o 4or one or more in the oxide of holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium; Described oxide is preferably nanoparticle; More preferably, described nuclear magnetic resonance material is selected from one or both in ferroso-ferric oxide or iron sesquioxide, the preferred γ iron sesquioxide of described iron sesquioxide.
5. according to the embolism materials compositions described in any one in claim 1 to 4, it is characterized in that, described biocompatible materials is polyvinyl alcohol, and preferably, the mean molecule quantity of described polyvinyl alcohol is 1,000-500,000D, preferably 10,000-150,000D; Alcoholysis degree is 50-100%, preferably 75-100%;
Preferably, described embolism materials compositions is Polyvinyl Alcohol Embolization microcapsule, and the reactant feed of described Polyvinyl Alcohol Embolization microcapsule comprises: 1 weight account polyethylene alcohol, the roentgenopaque material of 0.5-7.5 weight portion, 0.2-5 weight portion nuclear magnetic resonance material, 1-5.5 weight portion inorganic salt, 4-15 weight portion cross-linking agent, 0.9-13.1 weight portion catalyst and 0-3 weight portion medicine;
Preferably, described embolism materials compositions is Polyvinyl Alcohol Embolization microcapsule, and described Polyvinyl Alcohol Embolization microcapsule reactant feed comprises: the not saturating X ray material of 1 weight account polyethylene alcohol, 1-6.5 weight portion, 0.7-4.5 weight portion nuclear magnetic resonance material, 2.5-3.5 weight portion inorganic salt, 6-11 weight portion cross-linking agent, 5.8-13.1 weight portion catalyst and 0.5-1.5 weight portion medicine;
Preferably, described embolism materials compositions is Polyvinyl Alcohol Embolization microsphere, and the reactant feed of described Polyvinyl Alcohol Embolization microsphere comprises: 1 weight account polyethylene alcohol, the roentgenopaque material of 2-8 weight portion and 0.5-4 weight portion nuclear magnetic resonance material, 0.015-0.31 weight portion inorganic salt, 0.6-2.3 weight portion cross-linking agent, 0.5-1.8 weight portion catalyst, 0.1-2.5 weight portion surfactant, 5-60 weight portion and the immiscible organic solvent of water and 0-6 weight portion medicine;
Preferably, described embolism materials compositions is Polyvinyl Alcohol Embolization microsphere, and the reactant feed of described Polyvinyl Alcohol Embolization microsphere comprises: 1 weight account polyethylene alcohol, the roentgenopaque material of 6-8 weight portion, 1-4 weight portion nuclear magnetic resonance material, 0.15-0.31 weight portion inorganic salt, 0.6-1.2 weight portion cross-linking agent, 0.8-1.5 weight portion catalyst, 0.6-2 weight portion surfactant, 10-50 weight portion and the immiscible organic solvent of water and 2-6 weight portion medicine.
6. according to the embolism materials compositions described in any one in claim 1 to 4, it is characterized in that, described biocompatible materials is gelatin;
Preferably, described embolism materials compositions is gelatin embolism microcapsule, and the reactant feed of described gelatin embolism microcapsule comprises: 1 weight portion gelatin, the roentgenopaque material of 1-9.5 weight portion, 0.5-5 weight portion nuclear magnetic resonance material, 0.3-1.5 weight portion cross-linking agent and 0-4.5 weight portion medicine;
Preferably, described embolism materials compositions is gelatin embolism microcapsule, and the reactant feed of described gelatin embolism microcapsule comprises: 1 weight portion gelatin, the roentgenopaque material of 2-3.5 weight portion, 0.8-3 weight portion nuclear magnetic resonance material, 1.1-1.5 weight portion cross-linking agent and 0.5-4.5 weight portion medicine;
Preferably, described embolism materials compositions is gelatin embolism microsphere, and the reactant feed of described gelatin embolism microsphere comprises: 1 weight portion gelatin, the roentgenopaque material of 0.8-8 weight portion, 0.3-3.5 weight portion nuclear magnetic resonance material, 0.1-3.7 weight portion cross-linking agent, 0.1-3.13 weight portion surfactant, 5-50 weight portion and the immiscible organic solvent of water and 0-4.5 weight portion medicine;
Preferably, described embolism materials compositions is gelatin embolism microsphere, and the reactant feed of described gelatin embolism microsphere comprises: 1 weight portion gelatin, the roentgenopaque material of 0.8-2.2 weight portion, 0.5-3.5 weight portion nuclear magnetic resonance material, 0.7-3.7 weight portion cross-linking agent, 0.39-1.87 weight portion surfactant, 10-40 weight portion and the immiscible organic solvent of water and 0.5-4.5 weight portion medicine.
7. according to the embolism materials compositions described in any one in claim 1 to 4, it is characterized in that, described biocompatible materials is the mixture of chitosan and sodium carboxymethyl cellulose;
Described embolism materials compositions is chitosan-carboxymethyl cellulose thromboembolism microcapsule, and the reactant feed of described chitosan-carboxymethyl cellulose thromboembolism microcapsule comprises: 1 weight portion biocompatible materials, the roentgenopaque oily liquids of 4-10 weight portion and 0.5-5 weight portion nuclear magnetic resonance material, 0.2-0.8 weight portion cross-linking agent and 0-4.5 weight portion medicine.
8. according to the embolism materials compositions described in any one in claim 5 to 7, it is characterized in that, for the preparation of the inorganic salt of Polyvinyl Alcohol Embolization microsphere, be selected from one or more in water solublity sodium salt, potassium salt or ammonium salt; One or more in preferred potassium chloride, sodium chloride or ammonium chloride, more preferably sodium chloride; For the preparation of the inorganic salt of Polyvinyl Alcohol Embolization microcapsule, be selected from one or more in sulfate, phosphate, silicate or acetate, one or both in preferably sulfuric acid sodium, aluminum sulfate, ammonium sulfate, sodium tripolyphosphate, more preferably sodium sulfate;
Preferably, described cross-linking agent is selected from one or more in formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or hexandial; Described catalyst is selected from one or more in hydrochloric acid, sulphuric acid, phosphoric acid, formic acid or acetic acid;
Preferably, described surfactant be selected from spans surfactant or the mixture that formed by spans surfactant and Tweens surfactant in one or both, preferred one or both in sorbester p17 or sorbester p37;
Described embolism microball with the immiscible organic solvent of water in prepare, described and the immiscible organic solvent of water are selected from one or more in mineral oil, vegetable oil, silicone oil, alkene, alcohol, aldehyde, amine, ether or ketone, preferred liquid paraffin or cyclohexane extraction;
Preferably, described medicine is selected from one or more in antitumor drug, local anaesthesia medicine, antipyretic-antalgic anti-inflammatory agent thing or antibiotic medicine;
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, Sorafenib, gefitinib, imatinib, PTK787 or its salt;
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;
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;
Preferably, described antibiotic medicine is selected from one or more in 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, lincomycin or its salt.
9. according to the preparation method of the embolism materials compositions described in any one in claim 1 to 8, described preparation method comprises the following steps:
Step a: biocompatible materials is mixed with to solution;
Step b: roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the solution of step a; Preferably, when roentgenopaque material is oily liquids, medicine and/or nuclear magnetic resonance material are dispersed in roentgenopaque material, obtain mixed liquor, then this mixed liquor is joined in the solution of step a;
Step c: adopt physical-chemical process, physical mechanical method or chemical method to make biocompatible materials generation polymerization, obtain embolism materials compositions.
10. the preparation method of embolism materials compositions according to claim 9, is characterized in that, described embolism materials compositions is Polyvinyl Alcohol Embolization microcapsule, and described Polyvinyl Alcohol Embolization microcapsule adopts following methods preparation:
Step a1: take the polyvinyl alcohol of formula ratio, be mixed with 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, the more preferably poly-vinyl alcohol solution of 0.025g/ml;
Step b1: roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the poly-vinyl alcohol solution of step a1, stir, obtain mixed liquor;
Step c1: the inorganic salt that takes formula ratio, be mixed with 0.1-0.4g/ml, preferred 0.21-0.29g/ml, more preferably the inorganic salt solution of 0.25g/ml, the cloud point temperature of poly-vinyl alcohol solution under lower than this condition, preferably under the bath temperature of cloud point temperature 5-15 ℃ lower than poly-vinyl alcohol solution under this condition, inorganic salt solution is joined in the mixed liquor of step b1, continue to stir and slowly heat up, when temperature is increased to cloud point temperature, add cross-linking agent and catalyst, isothermal curing 15-23h, preferred consolidation 21-23h, more preferably solidify 22h, filter, after washing, obtain Polyvinyl Alcohol Embolization microcapsule, or,
Described Polyvinyl Alcohol Embolization microcapsule adopts following methods preparation:
Step a2: take the polyvinyl alcohol of formula ratio, be mixed with 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, the more preferably poly-vinyl alcohol solution of 0.025g/ml;
Step b2: the inorganic salt that takes formula ratio, be mixed with 0.1-0.4g/ml, preferred 0.21-0.29g/ml, more preferably the inorganic salt solution of 0.25g/ml, inorganic salt solution is mixed with the poly-vinyl alcohol solution in step a2, add subsequently roentgenopaque material, nuclear magnetic resonance material and optional medicine, the cloud point temperature of poly-vinyl alcohol solution under lower than this condition, preferably under the bath temperature of cloud point temperature 5-15 ℃ lower than poly-vinyl alcohol solution under this condition, stir, obtain mixed liquor;
Step c2: continue to stir also and slowly heat up, when temperature is increased to cloud point temperature, add cross-linking agent and catalyst, isothermal curing 15-23h, preferred consolidation 21-23h, more preferably solidifies 22h, after filtering, washing, obtains Polyvinyl Alcohol Embolization microcapsule.
The preparation method of 11. embolism materials compositionss according to claim 9, is characterized in that, described embolism materials compositions is Polyvinyl Alcohol Embolization microsphere, and described Polyvinyl Alcohol Embolization microsphere adopts following methods preparation:
Step a3: the inorganic salt that takes formula ratio, be mixed with 0.0045-0.025g/ml, preferred 0.017-0.025g/ml, more preferably the inorganic salt solution of 0.02g/ml, the polyvinyl alcohol of formula ratio is dissolved in inorganic salt solution, obtaining polyvinyl alcohol concentration is 0.08-0.3g/ml, preferably 0.21-0.3g/ml, the more preferably solution of 0.21g/ml;
Step b3: under room temperature, roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the solution of step a3, stir, obtain mixed liquor;
Step c3: the mixed liquor impouring that step b3 is made containing surfactant with the immiscible organic solvent of water in, make Emulsion, add subsequently cross-linking agent and catalyst, under the mixing speed of 300-1500rpm and 30-65 ℃ of bath temperature, solidify 2-23h, preferably under the mixing speed of 550-650rpm and 30-45 ℃ of bath temperature, solidify 3.5-6h, more preferably under the mixing speed of 600rpm and 30 ℃ of bath temperatures, solidify 4h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing; Or in the mixed liquor of making at step b3, add cross-linking agent and catalyst, after stirring impouring containing surfactant with the immiscible organic solvent of water in, make Emulsion, then under the mixing speed of 300-1500rpm and 30-65 ℃ of bath temperature, solidify 2-23h, preferably under the mixing speed of 550-650rpm and 30-45 ℃ of bath temperature, solidify 3.5-6h, more preferably under the mixing speed of 600rpm and 30 ℃ of bath temperatures, solidify 4h, filter, obtain Polyvinyl Alcohol Embolization microsphere after washing.
The preparation method of 12. embolism materials compositionss according to claim 9, is characterized in that, described embolism materials compositions is gelatin embolism microcapsule or gelatin embolism microsphere; Described gelatin embolism microcapsule adopts following methods preparation:
Step a4: take the gelatin of formula ratio, by gelatin with making 0.005-0.1g/ml after distilled water swelling, preferably 0.005-0.035g/ml, the more preferably gelatin solution of 0.035g/ml;
Step b4:, roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the gelatin solution of step a4 preferably under 53 ℃ of water bath condition at 40-60 ℃, stir, obtain mixed liquor; Then regulate the pH value of mixed liquor to 3.5-4.1, preferably drip 0.1g/ml acetum and regulate the pH value of mixed liquor to 3.5-4.1, after microcapsule forms, add distilled water diluting, obtain microcapsule suspension;
Step c4: the microcapsule suspension that step b4 is obtained adds cross-linking agent to solidify 0.5-24h under ice-water bath condition, preferably 70min or 15h, obtain gelatin embolism microcapsule after filtering, washing;
Described gelatin embolism microsphere adopts following methods preparation:
Step a5: take the gelatin of formula ratio, by gelatin with making 0.08-0.35g/ml after distilled water swelling, preferably 0.15-0.30g/ml, the more preferably gelatin solution of 0.28g/ml;
Step b5:, roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the gelatin solution of step a5 preferably under 53 ℃ of water bath condition at 35-63 ℃, stir, obtain mixed liquor;
Step c5: the mixed liquor impouring that step b5 is made containing surfactant with the immiscible organic solvent of water in, make Emulsion, Emulsion is transferred to and in ice-water bath, stirred 5-60min, preferred 30min, add cross-linking agent, solidify 0.5-24h, preferably 70min or 15h, obtain gelatin embolism microsphere after filtering, washing.
The preparation method of 13. embolism materials compositionss according to claim 9, is characterized in that, described embolism materials compositions is chitosan-carboxymethyl cellulose thromboembolism microcapsule, and described chitosan-carboxymethyl cellulose thromboembolism sodium microcapsule adopts following methods preparation:
Step a6: the chitosan that takes formula ratio, preparation is containing the acetum of 0.006-0.009g/ml chitosan, take the sodium carboxymethyl cellulose of formula ratio, the sodium carboxymethyl cellulose solution of preparation 0.02-0.056g/ml, is mixed to get mixed solution by the acetum of chitosan and sodium carboxymethyl cellulose solution;
Step b6: roentgenopaque material, nuclear magnetic resonance material and optional medicine are joined in the mixed solution of step a6, stir, make mixed liquor, regulate the pH value of mixed liquor to 5.5-6.5, preferably with 0.1g/ml sodium hydroxide solution, regulate the pH value of Emulsion to 5.5-6.5, reaction 5-60min, preferably 20min;
Step c6: the reactant liquor in step b6 is placed in to ice-water bath, adds cross-linking agent, the preferred 1h of crosslinking curing 0.5-2h, obtains chitosan-carboxymethyl cellulose thromboembolism microcapsule after filtering, washing.
14. according to the embolism materials compositions described in any one in claim 1 to 8 for the preparation for the treatment of tumor, for example 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 of the medicine that stops blooding.
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