CN103550834B - 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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CN103550834B
CN103550834B CN201310512955.0A CN201310512955A CN103550834B CN 103550834 B CN103550834 B CN 103550834B CN 201310512955 A CN201310512955 A CN 201310512955A CN 103550834 B CN103550834 B CN 103550834B
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polyvinyl alcohol
material composition
solution
inorganic salt
embolism
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CN103550834A (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

Embolic material composition and preparation method and application thereof
Technical Field
The invention belongs to the field of interventional medicine, and particularly relates to an embolic material composition, and a preparation method and application thereof.
Background
The interventional embolization treatment is to introduce embolization agent into human body for local treatment via special guide wire, catheter and other precise instrument under the guide of medical imaging equipment. The embolism therapy has good curative effect on the treatment of hysteromyoma, liver cancer, kidney cancer, hemangioma, vascular malformation, hemostasis and the like, and becomes a replacement therapy of partial surgical treatment.
Currently, clinically used embolizing agents, such as irregular particle-type or microsphere-type embolization agents of polyvinyl alcohol, irregular particle-type or microsphere-type embolization agents of gelatin sponge, etc., cannot be directly detected by X-ray imaging equipment (including Digital contrast imaging (DSA) and Computed Tomography (CT)) and Magnetic Resonance Imaging (MRI). In practice, the position of the embolic agent and the endpoint of the embolism can only be indirectly inferred by examining the flow of the contrast agent through DSA. A recent clinical study has shown that 20% of cases with this approach to complete embolization of the uterine artery do not reach complete embolization, and that post-operative MRI examination of these patients shows that some of the uterine artery is still available. Therefore, the indirect judgment method cannot accurately judge the position of the embolic agent and the embolic endpoint in time, and affects the curative effect and safety of the embolic treatment.
In order to be able to carry out direct detection of the embolizing agent under X-ray imaging equipment, some embolizing materials that are opaque to X-rays are disclosed in the prior art, however, the presence of ionizing radiation in X-ray examination is particularly disadvantageous for embolization and review of uterine fibroids in young women.
Magnetic Resonance Imaging (MRI) is a new medical diagnostic tool developed in recent decades and is a safe, fast and accurate clinical diagnostic method. The diagnosis of various diseases is applicable, including diagnosis of some diseases applicable to embolism treatment, such as: arteriovenous malformation, liver cancer, hysteromyoma, etc. MRI has high spatial and temporal resolution, excellent contrast between normal and diseased tissue, no ionizing radiation compared to X-ray detection techniques, and has been developed to the point of being able to acquire high resolution images in real time. MRI has the disadvantage that it cannot be used for patients with electrically, magnetically and mechanically active implants (e.g. cardiac pacemakers, neurostimulators, cochlear implants or metal prostheses, etc.) in their body.
Therefore, how to provide an embolization material that can be directly detected by both X-ray imaging equipment and MRI to provide patients with more choices is a problem to be solved in the art.
Disclosure of Invention
In view of the above problems, it is an object of the present invention to provide an embolic material composition that can be directly detected not only by X-ray imaging equipment but also by MRI, and that facilitates the selection of a detection method by a doctor according to the condition of the patient and the condition of medical equipment.
Another object of the present invention is to provide a method for preparing the embolic material composition.
It is a further object of the present invention to provide the use of a composition of an embolic material.
To achieve the above objects, the present invention provides a composition of embolic material made from reactant materials comprising: the embolization material composition comprises a biocompatible material, an X-ray opaque substance and a magnetic resonance imaging substance, wherein the X-ray opaque substance and the magnetic resonance imaging substance are wrapped by the biocompatible material.
Further, the reactant feedstock comprises: 1 part by weight of biocompatible material, 0.5-10 parts by weight of X-ray opaque substance, 0.2-5 parts by weight of magnetic resonance imaging substance and 0-6 parts by weight of medicine; wherein the drug is encapsulated by a biocompatible material.
Further, the embolic material composition is a spherical and irregularly shaped microparticle, preferably a microcapsule or microsphere;
preferably, the particle size of the particles is 10-2000 μm, and the particle size of the particles can be selected from 50-100 μm, 100-300 μm, 300-500 μm, 500-700 μm, 700-900 μm, 900-1200 μm, 1200-1500 μm, etc., according to the actual requirement.
Further, the biocompatible material is selected from one or more of polyvinyl alcohol, alginic acid, alginate, chitosan, gelatin, acacia, starch derivatives, cellulose derivatives, polylactic acid, or a copolymer formed from lactic acid and glycolic acid, etc.;
preferably, the X-ray opaque substance is selected from one or both of an X-ray opaque oily liquid or an X-ray opaque solid, preferably an X-ray opaque oily liquid, more preferably one or both of iodized oil or iodophenyl ester; the X-ray opaque solid is selected from one or two of tantalum powder or barium sulfate;
preferably, the magnetic resonance imaging substance is selected from one or more of magnetic metal elements of iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium; preferably, the magnetic resonance imaging substance is selected from one or more of the oxides of the magnetic metal elements iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, more preferably Fe3O4、Fe2O3、MnFe2O4、CoFe2O4、NiFe2O4、DyFe2O4Or one or more oxides of holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium; the oxide is preferably a nanoparticle; more preferably, the magnetic resonance imaging substance is selected from ferroferric oxideOr ferric oxide, wherein the ferric oxide is preferably gamma ferric oxide.
Further, the biocompatible material is polyvinyl alcohol, preferably, the polyvinyl alcohol has an average molecular weight of 1,000-500,000D, preferably 10,000-150,000D; the alcoholysis degree is 50-100%, preferably 75-100%;
preferably, the embolism material composition is a polyvinyl alcohol embolism microcapsule, and reactant raw materials of the polyvinyl alcohol embolism microcapsule comprise: 1 weight part of polyvinyl alcohol, 0.5 to 7.5 weight parts of X-ray opaque substance, 0.2 to 5 weight parts of magnetic resonance imaging substance, 1 to 5.5 weight parts of inorganic salt, 4 to 15 weight parts of cross-linking agent, 0.9 to 13.1 weight parts of catalyst and 0 to 3 weight parts of medicine;
preferably, the embolism material composition is polyvinyl alcohol embolism microcapsule, and the reactant raw materials of the polyvinyl alcohol embolism microcapsule comprise: 1 weight part of polyvinyl alcohol, 1 to 6.5 weight parts of X-ray opaque substance, 0.7 to 4.5 weight parts of magnetic resonance imaging substance, 2.5 to 3.5 weight parts of inorganic salt, 6 to 11 weight parts of cross-linking agent, 5.8 to 13.1 weight parts of catalyst and 0.5 to 1.5 weight parts of medicine;
preferably, the embolism material composition is a polyvinyl alcohol embolism microsphere, and the reactant raw materials of the polyvinyl alcohol embolism microsphere comprise: 1 weight portion of polyvinyl alcohol, 2 to 8 weight portions of X-ray opaque substance and 0.5 to 4 weight portions of magnetic resonance imaging substance, 0.015 to 0.31 weight portion of inorganic salt, 0.6 to 2.3 weight portions of cross-linking agent, 0.5 to 1.8 weight portions of catalyst, 0.1 to 2.5 weight portions of surfactant, 5 to 60 weight portions of organic solvent which is not miscible with water and 0 to 6 weight portions of medicine;
preferably, the embolism material composition is a polyvinyl alcohol embolism microsphere, and the reactant raw materials of the polyvinyl alcohol embolism microsphere comprise: 1 weight portion of polyvinyl alcohol, 6 to 8 weight portions of X-ray opaque substance, 1 to 4 weight portions of magnetic resonance imaging substance, 0.15 to 0.31 weight portion of inorganic salt, 0.6 to 1.2 weight portions of cross-linking agent, 0.8 to 1.5 weight portions of catalyst, 0.6 to 2 weight portions of surfactant, 10 to 50 weight portions of organic solvent which is not mutually soluble with water and 2 to 6 weight portions of medicine.
Further, the biocompatible material is gelatin; preferably, the embolic material composition is a gelatin embolic microcapsule, and reactant raw materials of the gelatin embolic microcapsule comprise: 1 part by weight of gelatin, 1-9.5 parts by weight of X-ray opaque substance, 0.5-5 parts by weight of magnetic resonance imaging substance, 0.3-1.5 parts by weight of cross-linking agent and 0-4.5 parts by weight of drug;
preferably, the embolic material composition is a gelatin embolic microcapsule, and reactant raw materials of the gelatin embolic microcapsule comprise: 1 part by weight of gelatin, 2 to 3.5 parts by weight of X-ray opaque substance, 0.8 to 3 parts by weight of magnetic resonance imaging substance, 1.1 to 1.5 parts by weight of cross-linking agent and 0.5 to 4.5 parts by weight of drug;
preferably, the embolism material composition is gelatin embolism microsphere, and the reactant raw material of the gelatin embolism microsphere comprises: 1 part by weight of gelatin, 0.8-8 parts by weight of X-ray opaque substance, 0.3-3.5 parts by weight of magnetic resonance imaging substance, 0.1-3.7 parts by weight of cross-linking agent, 0.1-3.13 parts by weight of surfactant, 5-50 parts by weight of organic solvent immiscible with water and 0-4.5 parts by weight of drug;
preferably, the embolism material composition is gelatin embolism microsphere, and the reactant raw material of the gelatin embolism microsphere comprises: 1 weight portion of gelatin, 0.8 to 2.2 weight portions of X-ray opaque substance, 0.5 to 3.5 weight portions of magnetic resonance imaging substance, 0.7 to 3.7 weight portions of cross-linking agent, 0.39 to 1.87 weight portions of surfactant, 10 to 40 weight portions of organic solvent which is not mutually soluble with water and 0.5 to 4.5 weight portions of medicine.
Further, the biocompatible material is a mixture of chitosan and sodium carboxymethyl cellulose;
the embolism material composition is chitosan-carboxymethyl cellulose embolism microcapsule, and reactant raw materials of the chitosan-carboxymethyl cellulose embolism microcapsule comprise: 1 part by weight of biocompatible material, 4 to 10 parts by weight of X-ray opaque oily liquid, 0.5 to 5 parts by weight of magnetic resonance imaging substance, 0.2 to 0.8 part by weight of cross-linking agent and 0 to 4.5 parts by weight of medicine.
Preferably, the inorganic salt used for preparing the polyvinyl alcohol embolism microsphere is selected from one or more of water-soluble sodium salt, potassium salt or ammonium salt; preferably one or more of potassium chloride, sodium chloride, ammonium chloride, etc., more preferably sodium chloride; the inorganic salt used for preparing the polyvinyl alcohol embolism microcapsule is selected from one or more of sulfate, phosphate, silicate or acetate, preferably one or two of sodium sulfate, aluminum sulfate, ammonium sulfate, sodium tripolyphosphate and the like, and more preferably sodium sulfate;
preferably, the cross-linking agent is selected from one or more of formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or adipaldehyde; the catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid or acetic acid;
preferably, the surfactant is selected from one or two of span surfactants or a mixture of span surfactants and tween surfactants, preferably one or two of span 80 or span 85;
the embolism microsphere is prepared in an organic solvent immiscible with water, wherein the organic solvent immiscible with water is selected from one or more of mineral oil, vegetable oil, silicone oil, olefin, alcohol, aldehyde, amine, ether, ketone, terpene hydrocarbon, halogenated hydrocarbon, heterocyclic compound, nitrogen-containing compound or sulfur-containing compound, and the like, and is preferably liquid paraffin or cyclohexane;
preferably, the medicine is selected from one or more of antitumor drugs, local anesthetic drugs, antipyretic, analgesic and anti-inflammatory drugs or antibiotic drugs;
preferably, the antineoplastic drug is selected from one or more of adriamycin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel, docetaxel, 5-fluorouracil, pingyangmycin, Sunitinib (Sunitinib), Sorafenib (Sorafenib), Gefitinib (Gefitinib), Imatinib (Imatinib), vartanabib (Vatalanib) or salts thereof;
preferably, the local anesthetic is selected from one or more of procaine, chloroprocaine, hydroxyprocaine, tetracaine, paraethoxycaine, tetracaine, dicaine, lidocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, farocaine, quinicaine, phenacaine or salts thereof;
preferably, the antipyretic analgesic anti-inflammatory drug is selected from one or more of aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, phenoxyibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, acetaminophen, diclofenac, fenprophen, ketoprofen, ketorolac, tetrachlorofenamic acid, sulindac, tolmetin and the like;
preferably, the antibiotic drug is selected from one or more of a beta-lactam antibiotic (e.g., penicillin, oxacillin sodium, ampicillin sodium, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid or sulbactam), a tetracycline antibiotic (e.g., oxytetracycline, tetracycline or demecycline), an aminoglycoside antibiotic (streptomycin, kanamycin a, gentamycin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribostamin, kanamycin B, neomycin B or paromomycin), a macrolide antibiotic (e.g., erythromycin, roxithromycin, clarithromycin or azithromycin) or other antibiotic (e.g., chloramphenicol, cyclosporine or lincomycin) or a salt thereof, and the like.
The embolic material composition of the present invention can be stored in physiological saline or phosphate buffer, or lyophilized.
The method of use of the embolic material composition of the present invention is the same as that of the conventional embolic agent.
The invention further provides a preparation method of the embolic material composition, which comprises the following steps:
step a: preparing a biocompatible material into a solution;
step b: adding an X-ray opaque substance, a magnetic resonance imaging substance and optionally a drug to the solution of step a; preferably, when the X-ray opaque substance is an oily liquid, the drug and/or the magnetic resonance imaging substance are/is dispersed in the X-ray opaque substance to obtain a mixed solution, and then the mixed solution is added to the solution in the step a;
step c: the biocompatible material is polymerized by a physical-chemical method, a physical-mechanical method or a chemical method to obtain the embolic material composition.
Further, the embolism material composition is a polyvinyl alcohol embolism microcapsule, and the polyvinyl alcohol embolism microcapsule is prepared by the following method:
step a 1: weighing polyvinyl alcohol according to the formula ratio to prepare 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, more preferably 0.025g/ml polyvinyl alcohol solution;
step b 1: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional medicines into the polyvinyl alcohol solution obtained in the step a1, and stirring to obtain a mixed solution;
step c 1: weighing inorganic salt with the formula amount, preparing 0.1-0.4g/ml, preferably 0.21-0.29g/ml, more preferably 0.25g/ml inorganic salt solution, adding the inorganic salt solution into the mixed solution in the step b1 at a water bath temperature which is lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, preferably 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, continuously stirring and slowly heating, adding a cross-linking agent and a catalyst when the temperature is raised to the cloud point temperature, curing at constant temperature for 15-23h, preferably 21-23h, more preferably 22h, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule; or,
the polyvinyl alcohol embolism microcapsule is prepared by the following method:
step a 2: weighing polyvinyl alcohol according to the formula ratio to prepare 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, more preferably 0.025g/ml polyvinyl alcohol solution;
step b 2: weighing inorganic salt with the formula amount, preparing 0.1-0.4g/ml, preferably 0.21-0.29g/ml, more preferably 0.25g/ml inorganic salt solution, mixing the inorganic salt solution with the polyvinyl alcohol solution in the step a2, adding the X-ray opaque substance, the magnetic resonance imaging substance and the optional drug, and stirring at a water bath temperature which is lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, preferably 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition to obtain a mixed solution;
step c 2: and (3) continuing stirring and slowly raising the temperature, adding a cross-linking agent and a catalyst when the temperature is raised to the cloud point temperature, curing for 15-23h at constant temperature, preferably 21-23h, more preferably 22h, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
Further, the embolism material composition is polyvinyl alcohol embolism microsphere, and the polyvinyl alcohol embolism microsphere is prepared by the following method:
step a 3: weighing inorganic salt with a formula amount to prepare an inorganic salt aqueous solution with the formula amount of 0.0045-0.025g/ml, preferably 0.017-0.025g/ml, more preferably 0.02g/ml, and dissolving polyvinyl alcohol with the formula amount in the inorganic salt aqueous solution to obtain a solution with the polyvinyl alcohol concentration of 0.08-0.3g/ml, preferably 0.21-0.3g/ml, more preferably 0.21 g/ml;
step b 3: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional medicines into the solution obtained in the step a3 at room temperature, and stirring to obtain a mixed solution;
step c 3: b3, pouring the mixed solution into an organic solvent which contains a surfactant and is not miscible with water to prepare an emulsion, then adding a cross-linking agent and a catalyst, curing for 2-23h at the stirring speed of 300-1500rpm and the water bath temperature of 30-65 ℃, preferably curing for 3.5-6h at the stirring speed of 550-650rpm and the water bath temperature of 30-45 ℃, more preferably curing for 4h at the stirring speed of 600rpm and the water bath temperature of 30 ℃, and filtering and washing to obtain the polyvinyl alcohol embolism microsphere; or adding a cross-linking agent and a catalyst into the mixed solution prepared in the step b3, stirring uniformly, pouring into an organic solvent which contains a surfactant and is not miscible with water to prepare an emulsion, curing for 2-23h at the stirring speed of 300-1500rpm and the water bath temperature of 30-65 ℃, preferably curing for 3.5-6h at the stirring speed of 550-650rpm and the water bath temperature of 30-45 ℃, more preferably curing for 4h at the stirring speed of 600rpm and the water bath temperature of 30 ℃, filtering, and washing to obtain the polyvinyl alcohol embolism microsphere.
Further, the embolism material composition is gelatin embolism microcapsule or gelatin embolism microsphere; the gelatin embolism microcapsule is prepared by the following method:
step a 4: weighing gelatin with formula amount, swelling gelatin with distilled water, and making into gelatin solution of 0.005-0.1g/ml, preferably 0.005-0.035g/ml, more preferably 0.035 g/ml;
step b 4: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional drugs into the gelatin solution obtained in the step a4 under the water bath condition of 40-60 ℃, preferably 53 ℃, and stirring to obtain a mixed solution; then adjusting the pH value of the mixed solution to 3.5-4.1, preferably dropwise adding 0.1g/ml acetic acid solution to adjust the pH value of the mixed solution to 3.5-4.1, and after the microcapsule is formed, adding distilled water for dilution to obtain a microcapsule suspension;
step c 4: b, adding the microcapsule suspension obtained in the step b4 into a cross-linking agent under the condition of ice water bath, curing for 0.5-24h, preferably 70min or 15h, filtering and washing to obtain the gelatin embolism microcapsule;
when the crosslinking agent is formaldehyde, the step c4 specifically includes: adding formaldehyde into the microcapsule suspension obtained in the step b4 under the condition of ice water bath, stirring for 2-15min, preferably 10min, adjusting the pH value to 8-9, preferably dropwise adding 0.1g/ml sodium hydroxide solution to adjust the pH value to 8-9, curing for 0.5-24h, preferably 15h, filtering and washing to obtain the gelatin embolism microcapsule.
The gelatin embolism microsphere is prepared by the following method:
step a 5: weighing gelatin with formula amount, swelling gelatin with distilled water, and making into gelatin solution of 0.08-0.35g/ml, preferably 0.15-0.30g/ml, more preferably 0.28 g/ml;
step b 5: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional drugs into the gelatin solution obtained in the step a5 under the condition of 35-63 ℃ water bath, preferably 53 ℃, and stirring to obtain a mixed solution;
step c 5: and c, pouring the mixed solution prepared in the step b5 into an organic solvent which contains a surfactant and is not mutually soluble with water to prepare an emulsion, transferring the emulsion into an ice water bath, stirring for 5-60min, preferably 30min, adding a cross-linking agent, curing for 0.5-24h, preferably 70min or 15h, filtering and washing to obtain the gelatin embolism microsphere.
When the crosslinking agent is formaldehyde, the step c5 specifically includes: and c, pouring the mixed solution prepared in the step b5 into an organic solvent which contains a surfactant and is not miscible with water to prepare an emulsion, transferring the emulsion into an ice water bath, stirring for 5-60min, preferably 30min, adding formaldehyde, stirring for 2-15min, preferably 10min, adjusting the pH value to 8-9, preferably dropwise adding 0.1g/ml sodium hydroxide solution to adjust the pH value to 8-9, curing for 0.5-24h, preferably 15h, filtering, and washing to obtain the gelatin embolism microsphere.
Further, the embolism material composition is chitosan-carboxymethyl cellulose embolism microcapsule, and the chitosan-carboxymethyl cellulose embolism sodium microcapsule is prepared by adopting the following method:
step a 6: weighing chitosan with a formula amount, preparing an acetic acid solution containing chitosan with the formula amount of 0.006-0.009g/ml, weighing sodium carboxymethylcellulose with the formula amount, preparing a sodium carboxymethylcellulose aqueous solution with the formula amount of 0.02-0.056g/ml, and mixing the acetic acid solution of chitosan with the sodium carboxymethylcellulose aqueous solution to obtain a mixed solution;
step b 6: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional medicines into the mixed solution obtained in the step a6, stirring to obtain a mixed solution, adjusting the pH value of the mixed solution to 5.5-6.5, preferably adjusting the pH value of the emulsion to 5.5-6.5 by using 0.1g/ml sodium hydroxide solution, and reacting for 5-60min, preferably 20 min;
step c 6: and c, placing the reaction solution in the step b6 in an ice water bath, adding a cross-linking agent, carrying out cross-linking curing for 0.5-2h, preferably 1h, filtering and washing to obtain the chitosan-carboxymethyl cellulose embolism microcapsule.
The invention further provides application of the embolism material composition in preparing a medicament for treating tumors, such as liver cancer, colorectal cancer liver metastasis, kidney cancer, lung cancer, prostatic cancer, ovarian cancer, uterine fibroids or breast malignant tumors, or vascular malformations or for stopping bleeding and the like.
Compared with the prior art, the embolic material composition of the invention has at least the following advantages:
1. the invention adopts the biocompatible material to wrap the X-ray-opaque substance and the magnetic resonance imaging substance to prepare the embolization material composition with the X-ray and magnetic resonance dual-imaging capability, so that the embolization material composition has good biocompatibility and can be directly detected by X-ray imaging equipment and MRI at the same time. Compared with the pure embolization agent developed by X-ray or MRI, the embolization material composition of the invention is not limited to be monitored by a single device, and can be monitored by an X-ray image device (such as CT and DSA) or MRI according to the device condition of a hospital and the self-requirement of a patient, so that the embolization effect can be conveniently checked in and after embolization, and the embolization material composition is more convenient to use.
2. Compared with the non-contrast embolic agent, the embolic material composition provided by the invention is convenient for a doctor to monitor the position of the embolic agent and the embolic endpoint during and after the embolization, and improves the treatment effect and safety.
3. The embolism material composition can be loaded with drugs and can be embolized to a specific part under the monitoring of X-ray imaging equipment (such as CT) or MRI, so that the targeted delivery of the loaded drugs is better realized; and the slow release of the medicine from the particles can be realized, higher medicine concentration can be maintained at the part of the embolism for a long time, and compared with perfusion treatment, the medicine can reduce the whole body toxic and side effects of the medicine and is beneficial to improving the curative effect of the embolism treatment.
4. The invention adopts biocompatible materials, X-ray opaque substances and magnetic resonance imaging substances to prepare the embolic material composition, has simple preparation process and low cost, and is suitable for large-scale industrial production.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is an optical micrograph of a polyvinyl alcohol embolization microsphere prepared according to example 5 of the present invention;
FIG. 2 is an in vitro CT detection image of the PVA embolization microspheres prepared in example 5 of the present invention;
FIG. 3 is an in vitro MRI test image of the PVA embolic microspheres prepared in example 5 of the present invention;
FIG. 4 is a CT image of the polyvinyl alcohol embolization microspheres prepared in example 5 of the present invention under the skin of a mouse;
FIG. 5 is an MRI image of the polyvinyl alcohol embolic microspheres prepared in example 5 of the present invention under the skin of a mouse;
FIG. 6 is the in vitro drug release profile of paclitaxel loaded polyvinyl alcohol embolization microspheres prepared according to example 8 of the present invention.
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials, reagents, materials and the like used in the following examples are all commercially available products unless otherwise specified.
Example 1Preparation of polyvinyl alcohol embolism microcapsule
1) Weighing 1g of polyvinyl alcohol to prepare 0.008g/ml of polyvinyl alcohol solution;
2) uniformly mixing 6.5g of iodized oil, 5g of ferroferric oxide nanoparticles and 1.5g of paclitaxel, adding the mixture into the polyvinyl alcohol solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) emulsion;
3) weighing 3.0g of sodium sulfate to prepare 0.21g/ml of sodium sulfate solution, adding the sodium sulfate solution into the emulsion obtained in the step 2) at a water bath temperature which is 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, continuously stirring and slowly heating, adding 11g of formaldehyde and 5.8g of sulfuric acid when the temperature is raised to the cloud point temperature, curing at constant temperature for 20 hours, standing for demixing, pouring out supernatant, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
Example 2Preparation of polyvinyl alcohol embolism microsphere
1) Weighing 0.31g of sodium chloride, preparing 0.025g/ml sodium chloride aqueous solution, and dissolving 1g of polyvinyl alcohol in the sodium chloride aqueous solution to obtain solution with the polyvinyl alcohol concentration of 0.08 g/ml;
2) dispersing 2g of ferric oxide nanoparticles and 6g of paclitaxel in 8g of iodized oil to obtain a mixed solution, then adding the mixed solution into the polyvinyl alcohol solution obtained in the step 1) at room temperature, and stirring to prepare an oil-in-water (o/w) type emulsion;
3) pouring the emulsion prepared in the step 2) into 60g of liquid paraffin containing 2.5g of span 85 to prepare oil-in-water (o/w/o) composite emulsion, then adding 0.6g of glutaraldehyde and 0.5g of sulfuric acid, curing for 2h at the stirring speed of 300rpm and the water bath temperature of 35 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
Example 3Preparation of gelatin embolism microcapsule
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.03 g/ml;
2) dispersing 0.5g of sorafenib and 3g of ferroferric oxide in 3.5g of iodized oil to obtain a mixed solution, adding the obtained mixed solution into the gelatin solution obtained in the step 1) under the condition of water bath at 40 ℃, stirring to prepare an oil-in-water (o/w) type emulsion, then dropwise adding 0.1g/ml of acetic acid solution to adjust the pH value of the emulsion to 3.5-4.1, observing the formation of microcapsules under a microscope, and adding distilled water to dilute to obtain a microcapsule suspension;
3) adding 1.5g of formaldehyde into the microcapsule suspension obtained in the step 2) under the ice-water bath condition, stirring for 2min, dropwise adding 0.1g/ml of sodium hydroxide solution, adjusting the pH value to 8-9, curing for 15h, standing for layering, pouring out a supernatant, filtering and washing to obtain the gelatin embolism microcapsule.
Example 4Preparation of polyvinyl alcohol embolism microsphere
1) Weighing 0.15g of sodium chloride, preparing 0.018g/ml sodium chloride aqueous solution, dissolving 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and preparing solution with the polyvinyl alcohol concentration of 0.12 g/ml;
2) dispersing 4g of ferric oxide nanoparticles and 1.5g of sorafenib in 6g of iodophenyl ester to obtain a mixed solution, adding the mixed solution into the polyvinyl alcohol solution obtained in the step 1) at room temperature, and stirring to prepare an oil-in-water (o/w) emulsion;
3) pouring the emulsion prepared in the step 2) into 17g of castor oil containing 0.4g of span 85 to prepare oil-in-water (o/w/o) type multiple emulsion, then adding 0.8g of formaldehyde and 0.6g of sulfuric acid, curing for 7 hours at the stirring speed of 1500rpm and the water bath temperature of 45 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
Example 5Preparation of polyvinyl alcohol embolism microsphere
1) Weighing 0.17g of sodium chloride, preparing 0.025g/ml sodium chloride aqueous solution, and dissolving 1g of polyvinyl alcohol in the sodium chloride aqueous solution to obtain solution with the polyvinyl alcohol concentration of 0.15 g/ml;
2) mixing 7g of iodized oil and 1.7g of ferroferric oxide nano particles uniformly at room temperature, adding the mixture into the polyvinyl alcohol solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) emulsion;
3) adding 0.9g of formaldehyde and 0.8g of sulfuric acid into the emulsion prepared in the step 2), quickly and uniformly stirring, pouring into 50g of liquid paraffin containing 2g of span 80 to prepare oil-in-water (o/w/o) type multiple emulsion, curing for 4 hours at the stirring speed of 750rpm and the water bath temperature of 30 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
The morphology of the polyvinyl alcohol embolization microspheres prepared above under an optical microscope is shown in fig. 1. As shown in figure 1, the prepared polyvinyl alcohol embolism microsphere is regular spherical, has good dispersibility and does not have bonding and agglomeration phenomena.
Example 6Preparation of gelatin embolism microsphere
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.3 g/ml;
2) 0.5g of MnFe is added under the condition of water bath at 53 DEG C2O4Dispersing in 1.2g iodized oil to obtain a mixed solution, adding the mixed solution into the gelatin solution obtained in the step 1), and stirring to obtain an oil-in-water (o/w) emulsion;
3) pouring the emulsion prepared in the step 2) into 10g cyclohexane containing 0.39g span 80 to prepare oil-in-water (o/w/o) emulsion, transferring the emulsion into an ice-water bath, continuously stirring for 30min, adding 0.2g formaldehyde, stirring for 2min, dropwise adding 0.1g/ml sodium hydroxide solution, adjusting the pH value to 8-9, curing for 10h, standing for layering, pouring out supernatant, filtering and washing to obtain the gelatin embolism microsphere.
Example 7Preparation of chitosan-carboxymethyl cellulose embolism microcapsule
1) Weighing 0.1g of chitosan to prepare an acetic acid solution containing 0.006g/ml of chitosan, weighing 0.9g of sodium carboxymethylcellulose to prepare a sodium carboxymethylcellulose aqueous solution of 0.056g/ml, and mixing the acetic acid solution of chitosan and the sodium carboxymethylcellulose aqueous solution to obtain a mixed solution;
2) 4g of iodized oil and 0.5g of ferric oxide nanoparticles are uniformly mixed and then added into the mixed solution in the step 1), and the mixture is magnetically stirred to prepare an oil-in-water (o/w) emulsion; adjusting the pH value of the emulsion to 5.5-6.5 with 0.1g/ml sodium hydroxide solution, and reacting for 5 min;
3) and (3) placing the reaction solution obtained in the step 2) in an ice water bath, adding 0.2g of glutaraldehyde, crosslinking and curing for 0.5h, standing for layering, pouring out supernatant, filtering and washing to obtain the chitosan-carboxymethyl cellulose embolism microcapsule.
Example 8Preparation of polyvinyl alcohol embolism microsphere
1) Weighing 0.015g of sodium chloride, preparing 0.0045g/ml of sodium chloride aqueous solution, and dissolving 1g of polyvinyl alcohol in the sodium chloride aqueous solution to obtain a solution with the polyvinyl alcohol concentration of 0.3 g/ml;
2) dispersing 1.2g of paclitaxel and 0.8g of ferroferric oxide nanoparticles in 2.2g of iodized oil at room temperature to prepare a mixed solution, adding the mixed solution into the polyvinyl alcohol solution obtained in the step 1) to prepare an oil-in-water (o/w) type emulsion;
3) adding 2.3g of glutaraldehyde and 1.8g of sulfuric acid into the emulsion prepared in the step 2), uniformly mixing, pouring into 5g of liquid paraffin containing 0.1g of span 85, curing for 16h at 550rpm and 55 ℃ in a water bath, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
Example 9Preparation of gelatin embolism microcapsule
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.1 g/ml;
2) dispersing 0.8g of gamma ferric oxide in 1g of iodized oil under the condition of water bath at 50 ℃ to prepare a mixed solution, adding the mixed solution into the gelatin solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) type emulsion; then 0.1g/ml acetic acid solution is dripped to adjust the pH value of the emulsion to 3.5-4.1, and after the formation of the microcapsule is observed under a microscope, distilled water is added to dilute the solution to obtain microcapsule suspension;
3) adding 0.3g of glutaraldehyde into the microcapsule suspension obtained in the step 2) under the condition of ice water bath, curing for 70min, standing for layering, pouring out supernatant, filtering and washing to obtain the gelatin embolism microcapsule.
Example 10Preparation of polyvinyl alcohol embolism microcapsule
1) Weighing 1g of polyvinyl alcohol to prepare 0.0035g/ml of polyvinyl alcohol solution;
2) mixing 7g of iodized oil, 0.5g of tantalum powder, 4.5g of ferroferric oxide nano particles and 3g of paclitaxel uniformly, adding the mixture into the polyvinyl alcohol solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) type emulsion;
3) weighing 5.5g of sodium sulfate to prepare 0.1g/ml of sodium sulfate solution, adding the sodium sulfate solution into the emulsion obtained in the step 2) at a water bath temperature which is 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, continuously stirring and slowly heating, adding 15g of formaldehyde and 13.1g of sulfuric acid when the temperature is raised to the cloud point temperature, curing at constant temperature for 23 hours, standing for layering, pouring out supernatant, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
Example 11Preparation of polyvinyl alcohol embolism microcapsule
1) Weighing 1g of polyvinyl alcohol to prepare 0.025g/ml of polyvinyl alcohol solution;
2) weighing 2.5g of sodium sulfate to prepare 0.29g/ml of sodium sulfate solution, mixing the sodium sulfate solution with the polyvinyl alcohol solution obtained in the step 1), then adding 2.1g of iodized oil and 1.7g of ferroferric oxide nano particles which are uniformly mixed, and stirring at a water bath temperature which is 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition to obtain an oil-in-water (o/w) emulsion;
3) and (3) continuously stirring and slowly heating, adding 8g of formaldehyde and 1.8g of hydrochloric acid when the temperature rises to the cloud point temperature, curing at a constant temperature for 23 hours, standing for layering, pouring out supernatant, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
Example 12Preparation of polyvinyl alcohol embolism microcapsule
1) Weighing 1g of polyvinyl alcohol to prepare 0.015g/ml of polyvinyl alcohol solution;
2) weighing 3.5g of sodium sulfate to prepare 0.262g/ml of sodium sulfate solution, mixing the sodium sulfate solution with the polyvinyl alcohol solution obtained in the step 1), then adding 3.5g of iodized oil, 2.4g of ferroferric oxide nanoparticles and 1.1g of adriamycin which are uniformly mixed, and stirring at a water bath temperature which is 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition to obtain an oil-in-water (o/w) emulsion;
3) and (3) continuously stirring and slowly heating, adding 10g of formaldehyde and 11g of hydrochloric acid when the temperature rises to the cloud point temperature, curing at constant temperature for 20 hours, standing for layering, pouring out supernatant, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
Example 13Preparation of polyvinyl alcohol embolism microcapsule
1) Weighing 1g of polyvinyl alcohol to prepare 0.05g/ml of polyvinyl alcohol solution;
2) dispersing 0.2g of ferroferric oxide nano particles in 0.5g of iodized oil to obtain a mixed solution, adding the mixed solution into the polyvinyl alcohol solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) emulsion;
3) weighing 1g of sodium tripolyphosphate, preparing 0.25g/ml of sodium tripolyphosphate solution, adding the sodium tripolyphosphate solution into the emulsion obtained in the step 2) at a water bath temperature which is 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, continuously stirring and slowly heating, adding 4g of formaldehyde and 0.9g of sulfuric acid when the temperature is raised to the cloud point temperature, curing at constant temperature for 15h, standing for layering, pouring out supernatant, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
Example 14Preparation of polyvinyl alcohol embolism microsphere
1) Weighing 0.043g of sodium chloride, preparing 0.01g/ml sodium chloride aqueous solution, and dissolving 1g of polyvinyl alcohol in the sodium chloride aqueous solution to obtain solution with the polyvinyl alcohol concentration of 0.23 g/ml;
2) uniformly mixing 2.8g of iodized oil, 1.2g of ferroferric oxide nanoparticles and 1.5g of paclitaxel at room temperature, adding the mixture into the polyvinyl alcohol solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) type emulsion;
3) adding 1.2g of glutaraldehyde and 1.1g of sulfuric acid into the emulsion prepared in the step 2), uniformly mixing, pouring into 11g of liquid paraffin containing 0.4g of span 85, curing for 23 hours at 600rpm and 65 ℃ water bath temperature, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
Example 15Preparation of gelatin embolism microcapsule
1) Weighing 1g of gelatin, swelling the gelatin by distilled water to prepare a gelatin solution of 0.035 g/ml;
2) under the condition of water bath at 60 ℃, 1.5g of iodized oil, 0.5g of tantalum powder, 0.5g of ferroferric oxide nano particles and 0.5g of sorafenib are uniformly mixed and then added into the gelatin solution in the step 1), stirring is carried out to prepare a mixed solution, then 0.1g/ml of acetic acid solution is dripped to adjust the pH value of the emulsion to 3.5-4.1, and after the formation of the micro-capsules is observed under a microscope, distilled water is added for dilution to obtain micro-capsule suspension;
3) adding 0.1g of formaldehyde into the microcapsule suspension obtained in the step 2) under the ice-water bath condition, stirring for 15min, dropwise adding 0.1g/ml of sodium hydroxide solution, adjusting the pH value to 8-9, curing for 10h, standing for layering, pouring out a supernatant, filtering and washing to obtain the gelatin embolism microcapsule.
Example 16Preparation of gelatin embolism microsphere
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.28 g/ml;
2) under the condition of water bath at 45 ℃, 2g of iodized oil, 0.2g of tantalum powder, 1g of ferroferric oxide nano particles and 1g of paclitaxel are uniformly mixed and then added into the gelatin solution in the step 1) and stirred to prepare a mixed solution;
3) pouring the emulsion prepared in the step 2) into 25g of liquid paraffin containing 0.51g of span 80 to prepare oil-in-water (w/o) emulsion, transferring the emulsion into an ice-water bath, continuously stirring for 5min, adding 0.7g of glutaraldehyde, curing for 70min, standing for layering, pouring out supernatant, filtering and washing to obtain the gelatin embolism microsphere.
Example 17Preparation of gelatin embolism microsphere
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.08 g/ml;
2) under the condition of water bath at 63 ℃, 8g of iodized oil, 3.5g of ferroferric oxide nano particles and 4.5g of paclitaxel are uniformly mixed and then added into the gelatin solution in the step 1) to be stirred to prepare an oil-in-water (o/w) type emulsion;
3) pouring the emulsion prepared in the step 2) into 50g of liquid paraffin containing 3.13g of span 80 to prepare oil-in-water-in-oil (o/w/o) emulsion, transferring the emulsion into an ice-water bath, continuously stirring for 60min, adding 3.7g of formaldehyde, stirring for 10min, dropwise adding 0.1g/ml of sodium hydroxide solution, adjusting the pH value to 8-9, curing for 15h, standing for layering, pouring out supernatant, filtering and washing to obtain the gelatin embolism microsphere.
Example 18Preparation of gelatin embolism microsphere
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.35 g/ml;
2) under the condition of 35 ℃ water bath, 0.8g of iodized oil and 0.3g of DyFe2O4Uniformly mixing the nano particles and 0.5g of sorafenib, adding the mixture into the gelatin solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) emulsion;
3) pouring the emulsion prepared in the step 2) into 5g of liquid paraffin containing 0.1g of span 80 to prepare oil-in-water-in-oil (o/w/o) emulsion, transferring the emulsion into an ice-water bath, continuously stirring for 20min, adding 0.1g of formaldehyde, stirring for 15min, dropwise adding 0.1g/ml of sodium hydroxide solution, adjusting the pH value to 8-9, curing for 24h, standing for layering, pouring out supernatant, filtering and washing to obtain the gelatin embolism microsphere.
Example 19Preparation of chitosan-carboxymethyl cellulose embolism microcapsule
1) Weighing 0.5g of chitosan to prepare an acetic acid solution containing 0.009g/ml of chitosan, weighing 0.5g of sodium carboxymethylcellulose to prepare a sodium carboxymethylcellulose aqueous solution of 0.035g/ml, and mixing the acetic acid solution of chitosan and the sodium carboxymethylcellulose aqueous solution to obtain a mixed solution;
2) uniformly mixing 5g of iodized oil, 2.5g of ferric oxide nanoparticles and 2.4g of cisplatin, adding the mixture into the mixed solution obtained in the step 1), and magnetically stirring to prepare an oil-in-water (o/w) emulsion; adjusting the pH value of the emulsion to 5.5-6.5 with 0.1g/ml sodium hydroxide solution, and reacting for 20 min;
3) and (3) placing the reaction solution obtained in the step 2) in an ice water bath, adding 0.8g of glutaraldehyde, crosslinking and curing for 2 hours, standing and layering, pouring out supernatant, filtering and washing to obtain the chitosan-carboxymethyl cellulose embolism microcapsule.
Example 20Preparation of polyvinyl alcohol embolism microcapsule
1) Weighing 1g of polyvinyl alcohol to prepare 0.04g/ml of polyvinyl alcohol solution;
2) 1g of iodized oil, 0.7g of ferroferric oxide nano particles and 0.2g of docetaxel are uniformly mixed and then added into the polyvinyl alcohol solution obtained in the step 1), and the mixture is stirred to prepare an oil-in-water (o/w) type emulsion;
3) weighing 2g of aluminum sulfate to prepare 0.4g/ml of aluminum sulfate solution, adding the aluminum sulfate solution into the emulsion obtained in the step 2) at the water bath temperature which is 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, continuously stirring and slowly heating, adding 6g of formaldehyde and 9.5g of sulfuric acid when the temperature is raised to the cloud point temperature, curing at constant temperature for 21 hours, standing for layering, pouring out supernatant, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
Example 21Preparation of polyvinyl alcohol embolism microcapsule
1) Weighing 1g of polyvinyl alcohol, and preparing 0.035g/ml polyvinyl alcohol solution;
2) uniformly mixing 1.5g of iodized oil, 1g of ferroferric oxide nanoparticles and 0.5g of sorafenib, adding the mixture into the polyvinyl alcohol solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) type emulsion;
3) weighing 1g of ammonium sulfate to prepare 0.175g/ml of ammonium sulfate solution, adding the ammonium sulfate solution into the emulsion obtained in the step 2) at a water bath temperature which is 5-15 ℃ lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, continuously stirring and slowly heating, adding 8g of formaldehyde and 3.1g of sulfuric acid when the temperature is raised to the cloud point temperature, curing at a constant temperature for 22 hours, standing for layering, pouring out supernatant, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
Example 22Preparation of polyvinyl alcohol embolism microsphere
1) Weighing 0.081g of sodium chloride, preparing 0.017g/ml of sodium chloride aqueous solution, and dissolving 1g of polyvinyl alcohol in the sodium chloride aqueous solution to obtain a solution with the polyvinyl alcohol concentration of 0.21 g/ml;
2) uniformly mixing 3g of iodized oil, 1g of ferric oxide nanoparticles and 2g of paclitaxel at room temperature, adding into the polyvinyl alcohol solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) emulsion;
3) pouring the emulsion prepared in the step 2) into 14g cyclohexane containing 0.6g span 85 to prepare oil-in-water (o/w/o) composite emulsion, then adding 1.1g glutaraldehyde and 0.9g sulfuric acid, curing for 6h at the stirring speed of 650rpm and the water bath temperature of 40 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
Example 23Preparation of polyvinyl alcohol embolism microsphere
1) Weighing 0.074g of sodium chloride, preparing 0.02g/ml sodium chloride aqueous solution, and dissolving 1g of polyvinyl alcohol in the sodium chloride aqueous solution to obtain solution with the polyvinyl alcohol concentration of 0.27 g/ml;
2) uniformly mixing 2g of iodized oil, 0.5g of ferric oxide nanoparticles and 1g of paclitaxel at room temperature, adding into the polyvinyl alcohol solution obtained in the step 1), and stirring to prepare an oil-in-water (o/w) emulsion;
3) pouring the emulsion prepared in the step 2) into 10g of liquid paraffin containing 0.7g of span 85 to prepare oil-in-water-in-oil (o/w/o) multiple emulsion, then adding 1.4g of glutaraldehyde and 1.5g of sulfuric acid, curing for 3.5h at the stirring speed of 900rpm and the water bath temperature of 45 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
Example 24Preparation of gelatin embolism microcapsule
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.025 g/ml;
2) under the condition of water bath at 46 ℃, 2.5g of iodized oil, 1g of ferroferric oxide nano particles and 1.5g of sorafenib are uniformly mixed and then added into the gelatin solution in the step 1), the mixture is stirred to prepare an oil-in-water (o/w) type emulsion, then 0.1g/ml of acetic acid solution is dripped to adjust the pH value of the emulsion to 3.5-4.1, and after the formation of the micro-capsules is observed under a microscope, distilled water is added for dilution to obtain micro-capsule suspension;
3) adding 1.1g of formaldehyde into the microcapsule suspension obtained in the step 2) under the ice-water bath condition, stirring for 10min, dropwise adding 0.1g/ml of sodium hydroxide solution, adjusting the pH value to 8-9, curing for 24h, standing for layering, pouring out a supernatant, filtering and washing to obtain the gelatin embolism microcapsule.
Example 25Preparation of gelatin embolism microcapsule
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.005 g/ml;
2) under the condition of water bath at 53 ℃, 9.5g of iodized oil, 5g of ferroferric oxide nano particles and 4.5g of sorafenib are uniformly mixed and then added into the gelatin solution in the step 1), the mixture is stirred to prepare an oil-in-water (o/w) type emulsion, then 0.1g/ml of acetic acid solution is dripped to adjust the pH value of the emulsion to 3.5-4.1, and after the formation of the micro-capsules is observed under a microscope, distilled water is added for dilution to obtain micro-capsule suspension;
3) adding 1.3g of glutaraldehyde into the microcapsule suspension obtained in the step 2) under the condition of ice water bath, curing for 0.5h, standing for layering, pouring out supernatant, filtering and washing to obtain the gelatin embolism microcapsule.
Example 26Preparation of gelatin embolism microsphere
1) Weighing 1g of gelatin, swelling the gelatin by distilled water, and preparing a gelatin solution of 0.15 g/ml;
2) under the condition of water bath at 60 ℃, 1.6g of iodized oil, 0.7g of ferroferric oxide nano particles and 0.7g of sorafenib which are uniformly mixed are added into the gelatin solution in the step 1) and stirred to prepare oil-in-water (o/w) type emulsion;
3) pouring the emulsion prepared in the step 2) into 40g of liquid paraffin containing 1.87g of span 80 to prepare oil-in-water-in-oil (o/w/o) emulsion, transferring the emulsion into an ice-water bath, continuously stirring for 10min, adding 2g of glutaraldehyde, curing for 0.5h, standing for layering, pouring out supernatant, filtering and washing to obtain the gelatin embolism microsphere.
Example 27Preparation of chitosan-carboxymethyl cellulose embolism microcapsule
1) Weighing 0.4g of chitosan to prepare an acetic acid solution containing 0.007g/ml of chitosan, weighing 0.6g of sodium carboxymethylcellulose to prepare a sodium carboxymethylcellulose aqueous solution of 0.02g/ml, and mixing the acetic acid solution of chitosan and the sodium carboxymethylcellulose aqueous solution to obtain a mixed solution;
2) uniformly mixing 10g of iodized oil, 5g of ferric oxide nanoparticles and 4.5g of paclitaxel, adding the mixture into the mixed solution obtained in the step 1), and magnetically stirring to prepare an oil-in-water (o/w) emulsion; adjusting the pH value of the emulsion to 5.5-6.5 with 0.1g/ml sodium hydroxide solution, and reacting for 60 min;
3) and (3) placing the reaction solution obtained in the step 2) in an ice water bath, adding 0.5g of glutaraldehyde, crosslinking and curing for 1h, standing and layering, pouring out supernatant, filtering and washing to obtain the chitosan-carboxymethyl cellulose embolism microcapsule.
Comparative examplePreparation of blank control polyvinyl alcohol embolism microsphere
Except that no iodized oil and ferroferric oxide nano particles are added, the content of each component and the preparation process are the same as those of the embodiment 5, and the specific preparation method is as follows:
1) weighing 0.17g of sodium chloride, preparing 0.025g/ml sodium chloride aqueous solution, dissolving 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and preparing solution with polyvinyl alcohol concentration of 0.15 g/ml;
2) adding 0.9g of formaldehyde and 0.8g of sulfuric acid into the polyvinyl alcohol solution obtained in the step 1), and uniformly mixing to obtain a mixed solution; and pouring the mixed solution into 50g of liquid paraffin containing 2g of span 80 to prepare a water-in-oil (w/o) emulsion, solidifying for 4 hours at the stirring speed of 750rpm and the water bath temperature of 30 ℃, filtering and washing to obtain the blank control polyvinyl alcohol microspheres.
Test 1In vitro CT and MRI detection of embolic microspheres
In vitro CT and MRI tests were performed on the PVA embolization microspheres prepared in example 5 and the blank control PVA embolization microspheres prepared in the comparative example, respectively. The experimental procedure was as follows: preparing a 2% agar hot solution, pouring the solution into a culture dish to enable the liquid surface thickness to be 1.5cm, after the solution is cooled to form gel, respectively placing the polyvinyl alcohol embolism microspheres and the blank control polyvinyl alcohol embolism microspheres on the surface of the agar, pouring the solution into the agar hot solution with the thickness of 1cm again, cooling, and then respectively placing the surface dish under CT and 3T MRI for scanning, wherein the detection results under the CT and 3T MRI are respectively shown in figure 2 and figure 3: in fig. 2 and 3, the in vitro CT and 3T MRI detection results (the number of microspheres on the top and bottom sides is 1, 2, 3, 4, 5 respectively) of the pva embolic microsphere (right side) and the blank pva embolic microsphere (left side) are shown, respectively, and it can be seen from fig. 2 and 3 that the pva magnetic microsphere is clearly visible under CT and 3T MRI, but the blank pva embolic microsphere is not detected basically.
Test 2CT and MRI detection of embolic microspheres under mouse skin
100-300 μm microspheres were separated from the polyvinyl alcohol embolization microspheres prepared in example 5, and 2.5ml of the microspheres were suspended in 20ml of physiological saline containing 1% sodium carboxymethylcellulose, and 0.15ml was injected subcutaneously into mice. The mice were scanned under CT and 3T MRI, and the results of the CT and 3T MRI are shown in fig. 4 and 5, respectively. Fig. 4 shows a CT image of polyvinyl alcohol embolic microspheres subcutaneously in mice, with white arrows indicating injection sites. Fig. 5 shows MRI images of the polyvinyl alcohol embolic microspheres under the skin of a mouse, white bright spots outside the mouse in fig. 5 are vitamin E capsules, white arrows mark injection sites, and CT and MRI results show that the polyvinyl alcohol embolic microspheres can be detected at the subcutaneous injection sites of the mouse.
Test 3Embolization in microsphere
Microspheres with a particle size of 100-150 μm were screened from the polyvinylalcohol embolization microspheres prepared in example 5 and sterilized for future use. After 12h of fasting rabbits were anesthetized and mounted on the operating table, one carotid artery was isolated, and under Digital Subtraction Angiography (DSA), the left renal artery was selectively cannulated through the carotid artery with a 2.8F catheter and guidewire, and 0.15ml of microspheres were injected for renal embolization, and the DSA examination was performed on the left kidney both before and after embolization to determine whether the target vessel was occluded. And (4) carrying out CT and MRI detection after the operation, wherein the detection results of the CT and the MRI both show that the position of the microsphere is consistent with the DSA detection result.
Test 4Drug release experiment of drug-loaded embolic microspheres
The in vitro release of paclitaxel loaded polyvinyl alcohol embolic microspheres prepared in example 8 was determined using a T-tube method. The experimental procedure was as follows: 200ml of pH7.4 phosphate buffer as release medium were added to the T-tube, the buffer fluidity was 50ml/min, and the water bath temperature was 37 ℃. Placing 1ml of the microspheres at the bottom of a T-shaped tube, taking out 5ml of release medium respectively after 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, immediately supplementing isothermal and equal-volume fresh release medium, measuring the absorbance value at 227nm, and calculating the drug release amount according to a standard curve. The drug release curve of the paclitaxel-loaded polyvinyl alcohol embolization microsphere is shown in figure 6. As seen in fig. 6, the paclitaxel-loaded polyvinyl alcohol embolization microspheres released drug at a faster rate in the first 4 hours, released drug at about 45% cumulatively in 4 hours, and released drug at about 61% cumulatively in 24 hours.
The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined by the scope of the appended claims.

Claims (52)

1. A embolic material composition made from reactant feedstock comprising: the embolization material composition comprises a biocompatible material, an X-ray opaque substance, a magnetic resonance imaging substance and an optional drug, wherein the X-ray opaque substance and the magnetic resonance imaging substance are wrapped by the biocompatible material, and the drug is wrapped by the biocompatible material;
the embolism material composition is polyvinyl alcohol embolism microsphere, and reactant raw materials of the polyvinyl alcohol embolism microsphere comprise: 1 part by weight of polyvinyl alcohol, 2-8 parts by weight of X-ray opaque substance and 0.5-4 parts by weight of magnetic resonance imaging substance, 0.015-0.31 part by weight of inorganic salt, 0.6-2.3 parts by weight of cross-linking agent, 0.5-1.8 parts by weight of catalyst, 0.1-2.5 parts by weight of surfactant, 5-60 parts by weight of water-immiscible organic solvent and 0-6 parts by weight of drug, wherein the X-ray opaque substance is one or two of X-ray opaque oily liquid or X-ray opaque solid, the magnetic resonance material is one or more of magnetic metal elements of iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, the inorganic salt is one or more of water-soluble sodium salt, potassium salt or ammonium salt, and the cross-linking agent is one or more of formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or hexandialdehyde, the catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid or acetic acid, the surfactant is selected from one or two of span surfactants or a mixture consisting of span surfactants and tween surfactants, and the organic solvent immiscible with water is one or more of mineral oil, vegetable oil, silicone oil, olefin, alcohol, aldehyde, amine, ether or ketone;
or,
the embolism material composition is a polyvinyl alcohol embolism microcapsule, and reactant raw materials of the polyvinyl alcohol embolism microcapsule comprise: 1 weight portion of polyvinyl alcohol, 0.5 to 7.5 weight portions of X-ray opaque substance, 0.2 to 5 weight portions of magnetic resonance imaging substance, 1 to 5.5 weight portions of inorganic salt, 4 to 15 weight portions of cross-linking agent, 0.9 to 13.1 weight portions of catalyst and 0 to 3 weight portions of medicine, wherein the X-ray opaque substance is one or both of an X-ray opaque oily liquid or an X-ray opaque solid, the magnetic resonance material is selected from one or more of magnetic metal elements of iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, the inorganic salt is selected from one or more of sulfate, phosphate, silicate or acetate, the crosslinking agent is selected from one or more of formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or hexandialdehyde, and the catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid or acetic acid.
2. The embolic material composition of claim 1, wherein the microspheres or microcapsules have a particle size of 10-2000 μ ι η.
3. The embolic material composition of claim 1, wherein the drug is selected from one or more of an anti-tumor drug, a local anesthetic drug, an antipyretic, analgesic, anti-inflammatory drug, or an antibiotic drug.
4. The embolic material composition of claim 1, wherein the radiopaque substance is an oily liquid radiopaque for X-ray.
5. The embolic material composition of claim 4, wherein the radiopaque substance is one or both of iodized oil or iodophenyl ester.
6. The embolic material composition of claim 1, wherein the magnetic resonance imaging substance is selected from the group consisting of Fe3O4、Fe2O3、MnFe2O4、CoFe2O4、NiFe2O4、DyFe2O4Or one or more oxides of holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium.
7. The embolic material composition of claim 6, wherein the oxide is a nanoparticle.
8. The embolic material composition of claim 6, wherein the magnetic resonance imaging substance is selected from one or both of ferroferric oxide and ferric oxide.
9. The embolic material composition of claim 8, wherein the ferric oxide is gamma ferric oxide.
10. The embolic material composition of claim 1, wherein the polyvinyl alcohol has an average molecular weight of 1,000-500,000D.
11. The embolic material composition of claim 10, wherein the polyvinyl alcohol has an average molecular weight of 10,000-150,000D.
12. The embolic material composition of claim 1, wherein the polyvinyl alcohol has a degree of alcoholysis of from 50 to 100%.
13. The embolic material composition of claim 12, wherein the polyvinyl alcohol has an alcoholysis degree of 75-100%.
14. The embolic material composition of claim 1, wherein the embolic material composition is a polyvinyl alcohol embolic microcapsule having reactant materials comprising: 1 weight portion of polyvinyl alcohol, 1 to 6.5 weight portions of X-ray opaque substance, 0.7 to 4.5 weight portions of magnetic resonance imaging substance, 2.5 to 3.5 weight portions of inorganic salt, 6 to 11 weight portions of cross-linking agent, 5.8 to 13.1 weight portions of catalyst and 0.5 to 1.5 weight portions of medicine.
15. The embolic material composition of claim 1, wherein the embolic material composition is a polyvinyl alcohol embolic microsphere having reactant materials comprising: 1 weight portion of polyvinyl alcohol, 6 to 8 weight portions of X-ray opaque substance, 1 to 4 weight portions of magnetic resonance imaging substance, 0.15 to 0.31 weight portion of inorganic salt, 0.6 to 1.2 weight portions of cross-linking agent, 0.8 to 1.5 weight portions of catalyst, 0.6 to 2 weight portions of surfactant, 10 to 50 weight portions of organic solvent which is not mutually soluble with water and 2 to 6 weight portions of medicine.
16. The embolic material composition of claim 1, wherein the inorganic salt used to prepare the polyvinyl alcohol embolic microspheres is selected from one or more of potassium chloride, sodium chloride, or ammonium chloride.
17. The embolic material composition of claim 16, wherein the inorganic salt is sodium chloride.
18. The embolic material composition of claim 1, wherein the inorganic salt used to prepare the polyvinyl alcohol embolic microcapsules is selected from one or two of sodium sulfate, aluminum sulfate, ammonium sulfate, sodium tripolyphosphate.
19. The embolic material composition of claim 18, wherein the inorganic salt is sodium sulfate.
20. The embolic material composition of claim 1, wherein the surfactant is one or both of span 80 or span 85.
21. The embolic material composition of claim 1, wherein the water-immiscible organic solvent is liquid paraffin or cyclohexane.
22. The embolic material composition of claim 3, wherein the anti-tumor drug is selected from one or more of doxorubicin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel, docetaxel, 5-fluorouracil, pingyangmycin, sunitinib, sorafenib, gefitinib, imatinib, vatalanib, or salts thereof.
23. The embolic material composition of claim 3, wherein the local anesthetic drug is selected from one or more of procaine, chloroprocaine, hydroxyprocaine, tetracaine, paraethoxycaine, tetracaine, dicaine, lidocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, favicine, quinicaine, phenacaine, or salts thereof.
24. The embolic material composition of claim 3, wherein the antipyretic, analgesic, and anti-inflammatory drug is selected from one or more of aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, phenoxyibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, acetaminophen, diclofenac, fenprophen, ketoprofen, ketorolac, tetrachlorofenamic acid, sulindac, or tolmetin.
25. The embolic material composition of claim 3, wherein the antibiotic drug is selected from one or more of penicillin, oxacillin sodium, ampicillin sodium, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid, sulbactam, oxytetracycline, tetracycline, demeclocycline, streptomycin, kanamycin A, gentamicin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribomycin, kanamycin B, neomycin B, paromomycin, erythromycin, roxithromycin, clarithromycin, azithromycin, chloramphenicol, cyclosporine, lincomycin, or salts thereof.
26. The method for producing an embolic material composition according to any of claims 1 to 25,
the embolism material composition is characterized in that the embolism material composition is a polyvinyl alcohol embolism microcapsule, and the polyvinyl alcohol embolism microcapsule is prepared by the following method:
step a 1: weighing polyvinyl alcohol with the formula ratio to prepare 0.0035-0.05g/ml polyvinyl alcohol solution;
step b 1: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional medicines into the polyvinyl alcohol solution obtained in the step a1, and stirring to obtain a mixed solution;
step c 1: weighing inorganic salt with the formula amount, preparing 0.1-0.4g/ml inorganic salt solution, adding the inorganic salt solution into the mixed solution in the step b1 at the water bath temperature lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, continuously stirring and slowly heating, adding a cross-linking agent and a catalyst when the temperature is raised to the cloud point temperature, curing at constant temperature for 15-23h, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
27. The method according to claim 26, wherein in step a1, the polyvinyl alcohol is weighed to obtain a polyvinyl alcohol solution of 0.025-0.04 g/ml.
28. The method according to claim 27, wherein in step a1, the polyvinyl alcohol is weighed out to obtain a polyvinyl alcohol solution of 0.025 g/ml.
29. The method according to claim 26, wherein in step c1, the inorganic salt is weighed to obtain a solution of 0.21-0.29g/ml inorganic salt.
30. The method according to claim 29, wherein in step c1, the inorganic salt is weighed out to obtain a solution of 0.25g/ml inorganic salt.
31. The method of claim 26, wherein in step c1, the inorganic salt solution is added to the mixture of step b1 at a bath temperature of 5-15 ℃ below the cloud point temperature of the polyvinyl alcohol solution under the conditions.
32. The method for preparing the nano particles according to claim 26, wherein in the step c1, the nano particles are solidified for 21-23h at constant temperature.
33. The method for preparing the nano particles according to the claim 32, wherein in the step c1, the nano particles are cured for 22 hours at a constant temperature.
34. The method for preparing an embolic material composition according to any of claims 1 to 25, wherein the embolic material composition is a polyvinyl alcohol embolic microcapsule prepared by:
step a 2: weighing polyvinyl alcohol with the formula ratio to prepare 0.0035-0.05g/ml polyvinyl alcohol solution;
step b 2: weighing inorganic salt with the formula ratio, preparing 0.1-0.4g/ml inorganic salt solution, mixing the inorganic salt solution with the polyvinyl alcohol solution in the step a2, then adding the X-ray opaque substance, the magnetic resonance imaging substance and the optional drug, and stirring at a water bath temperature lower than the cloud point temperature of the polyvinyl alcohol solution under the condition to obtain mixed solution;
step c 2: and (3) continuously stirring and slowly heating, adding a cross-linking agent and a catalyst when the temperature rises to the cloud point temperature, curing for 15-23h at constant temperature, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
35. The method according to claim 34, wherein in step a2, the polyvinyl alcohol is weighed to obtain a polyvinyl alcohol solution of 0.025-0.04 g/ml.
36. The method according to claim 35, wherein in step a2, the polyvinyl alcohol is weighed out to obtain a polyvinyl alcohol solution of 0.025 g/ml.
37. The method according to claim 34, wherein in step b2, the inorganic salt is weighed out to obtain a solution of 0.21-0.29g/ml inorganic salt.
38. The method according to claim 37, wherein in step b2, the inorganic salt is weighed out to obtain a solution of 0.25g/ml inorganic salt.
39. The method of claim 34, wherein in step b2, the polyvinyl alcohol solution is stirred at a bath temperature of 5-15 ℃ below the cloud point temperature of the polyvinyl alcohol solution under the conditions.
40. The method for preparing the nano particles as claimed in claim 34, wherein in the step c2, the nano particles are solidified for 21-23h at constant temperature.
41. The method for preparing a nano material according to claim 40, wherein in the step c2, the nano material is cured for 22 hours at a constant temperature.
42. The method for preparing the embolic material composition of any of claims 1 to 25, wherein the embolic material composition is polyvinyl alcohol embolic microspheres prepared by:
step a 3: weighing inorganic salt with a formula amount to prepare an inorganic salt water solution with the concentration of 0.0045-0.025g/ml, and dissolving polyvinyl alcohol with the formula amount in the inorganic salt water solution to obtain a solution with the concentration of 0.08-0.3 g/ml;
step b 3: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional medicines into the solution obtained in the step a3 at room temperature, and stirring to obtain a mixed solution;
step c 3: b3, pouring the mixed solution into an organic solvent which contains a surfactant and is not mutually soluble with water to prepare an emulsion, then adding a cross-linking agent and a catalyst, curing for 2-23h at the stirring speed of 300-1500rpm and the water bath temperature of 30-65 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere; or adding a cross-linking agent and a catalyst into the mixed solution prepared in the step b3, uniformly stirring, pouring into an organic solvent which contains a surfactant and is not mutually soluble with water to prepare an emulsion, curing for 2-23h at the stirring speed of 300-1500rpm and the water bath temperature of 30-65 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
43. The method according to claim 42, wherein in step a3, the inorganic salt is weighed to obtain an aqueous solution of 0.017-0.025 g/ml.
44. The method according to claim 43, wherein in step a3, the inorganic salt is weighed out to obtain a formula amount to obtain an aqueous solution of 0.02g/ml inorganic salt.
45. The method according to claim 42, wherein in step a3, the polyvinyl alcohol is dissolved in an aqueous solution of an inorganic salt to obtain a solution having a polyvinyl alcohol concentration of 0.21-0.3 g/ml.
46. The method according to claim 45, wherein in step a3, the polyvinyl alcohol is dissolved in an aqueous solution of an inorganic salt to obtain a solution with a polyvinyl alcohol concentration of 0.21 g/ml.
47. The method as claimed in claim 42, wherein in step c3, the cross-linking agent and the catalyst are added and cured for 3.5-6h at a stirring speed of 550-650rpm and a water bath temperature of 30-45 ℃.
48. The preparation method of claim 47, wherein in the step c3, the cross-linking agent and the catalyst are added, the mixture is solidified for 4 hours at a stirring speed of 600rpm and a water bath temperature of 30 ℃, and the polyvinyl alcohol embolism microspheres are obtained after filtration and washing.
49. The method as claimed in claim 42, wherein in the step c3, the emulsion is prepared and then cured for 3.5-6h at a stirring speed of 550-650rpm and a water bath temperature of 30-45 ℃.
50. The method of claim 49, wherein in step c3, the emulsion is prepared and then cured for 4 hours at a stirring speed of 600rpm and a water bath temperature of 30 ℃.
51. Use of the embolic material composition of any of claims 1 to 25 in the manufacture of a medicament for treating a tumor or vascular malformation or for hemostasis.
52. The use according to claim 51, wherein the tumor is liver cancer, liver metastasis of colorectal cancer, kidney cancer, lung cancer, prostate cancer, ovarian cancer, uterine fibroids or breast malignancy.
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