CN103550834B - Embolism material composition as well as preparation method and use thereof - Google Patents

Abstract

The invention provides an embolic material composition and its preparation method and application. The embolic material composition is made of reactant raw materials, and the reactant raw materials include: biocompatible materials, X-ray-opaque substances and magnetic resonance Imaging substances, in the embolic material composition, X-ray-opaque substances and magnetic resonance imaging substances are wrapped by biocompatible materials. The embolic material composition of the present invention can not only be directly detected by X-ray imaging equipment, but also can be directly detected by MRI, which is convenient for doctors to choose a detection method according to the patient's own conditions and medical equipment conditions.

Description

A kind of embolic material composition and its preparation method and application

technical field

The invention belongs to the field of interventional medicine, and in particular relates to an embolic material composition, a preparation method and application thereof.

Background technique

Interventional embolization therapy refers to the introduction of embolic agents into the human body through precision instruments such as special guide wires and catheters for local treatment under the guidance of medical imaging equipment. Embolization therapy has achieved good results in the treatment of uterine fibroids, liver cancer, kidney cancer, hemangioma, vascular malformation and hemostasis, and has become an alternative to partial surgical treatment.

Currently clinically used embolic agents, such as polyvinyl alcohol irregular particles or microspheres, gelatin sponge irregular particles or microspheres, etc., cannot be detected by X-ray imaging equipment (including digital Subtraction Angiography, DSA) and computed tomography (Computed Tomography, CT)) and magnetic resonance imaging (Magnetic Resonance Imaging, MRI) direct detection. In practice, the location of the embolic agent and the end point of embolization can only be inferred indirectly by checking the flow of the contrast agent with DSA. A recent clinical study showed that 20% of the cases where the uterine artery was completely embolized by this method did not achieve complete embolization, and postoperative MRI examinations showed that some of the uterine arteries in these patients still had blood supply. Therefore, this indirect judgment method cannot timely and accurately judge the location of the embolic agent and the end point of embolization, which affects the efficacy and safety of embolization therapy.

In order to be able to directly detect embolic agents under X-ray imaging equipment, some X-ray-opaque embolic materials are disclosed in the prior art, but X-ray examinations have ionizing radiation, which is especially unfavorable for embolization of uterine fibroids in young women and review.

Magnetic resonance imaging (MRI) is a new medical diagnostic method developed in recent decades, and it is a safe, fast and accurate clinical diagnosis method. It is suitable for the diagnosis of various diseases, including some diseases suitable for embolization therapy, such as: arteriovenous malformation, liver cancer and uterine fibroids. MRI has high spatial and temporal resolution, excellent contrast between normal tissue and diseased tissue, no ionizing radiation compared with X-ray detection technology, and has been developed to the extent that it can acquire high-resolution images in real time. However, the disadvantage of MRI is that it cannot be used in patients with electrically, magnetically and mechanically active implants in the body (such as cardiac pacemakers, neurostimulators, cochlear implants or metal prosthetic eyes, etc.).

Therefore, how to provide an embolic material that can be directly detected by both X-ray imaging equipment and MRI so as to provide patients with more choices has become an urgent problem to be solved in this field.

Contents of the invention

In view of the above problems, an object of the present invention is to provide an embolic material composition, which can not only be directly detected by X-ray imaging equipment, but also can be directly detected by MRI. Select a detection method.

Another object of the present invention is to provide a preparation method of an embolic material composition.

Another object of the present invention is to provide an application of an embolic material composition.

In order to achieve the above object, the present invention provides an embolic material composition, which is made of reactant raw materials, said reactant raw materials include: biocompatible materials, X-ray-opaque substances and magnetic resonance imaging substances, said In the embolic material composition, the X-ray opaque material and the magnetic resonance imaging material are surrounded by a biocompatible material.

Further, the reactant raw materials include: 1 part by weight of biocompatible materials, 0.5-10 parts by weight of X-ray-opaque substances, 0.2-5 parts by weight of magnetic resonance imaging substances, and 0-6 parts by weight of drugs; wherein, The drug is encapsulated by biocompatible material.

Further, the embolic material composition is spherical and irregularly shaped particles, preferably microcapsules or microspheres;

Preferably, the particle size of the particles is 10-2000 μm, and the particle size of the particles can be selected as 50-100 μm, 100-300 μm, 300-500 μm, 500-700 μm, 700-900 μm, 900-1200 μm or 1200 μm according to actual needs. -1500μm etc.

Further, the biocompatible material is selected from polyvinyl alcohol, alginic acid, alginate, chitosan, gelatin, gum arabic, starch, starch derivatives, cellulose, cellulose derivatives, polylactic acid or One or more of the copolymers of lactic acid and glycolic acid;

Preferably, the X-ray-opaque substance is selected from one or both of X-ray-opaque oily liquids or X-ray-opaque solids, preferably X-ray-opaque oily liquids, more preferably iodized oil or One or both of iodophenyl esters; the X-ray-opaque solid is selected from one or both of tantalum powder or barium sulfate;

Preferably, the magnetic resonance imaging substance is selected from one or more of the compounds of magnetic metal elements iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium; preferably, the The magnetic resonance imaging substance is selected from one or more of the oxides of magnetic metal elements iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, more preferably Fe ₃ O ₄ , Fe ₂ O ₃ , MnFe ₂ O ₄ , CoFe ₂ O ₄ , NiFe ₂ O ₄ , DyFe ₂ O ₄ or one or more of the oxides of holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium; the oxide The substance is preferably a nanoparticle; more preferably, the magnetic resonance imaging substance is selected from one or both of ferric oxide and ferric oxide, and the ferric oxide is preferably gamma ferric oxide.

Further, the biocompatible material is polyvinyl alcohol, preferably, the average molecular weight of the polyvinyl alcohol is 1,000-500,000D, preferably 10,000-150,000D; the degree of alcoholysis is 50-100%, preferably 75- 100%;

Preferably, the embolic material composition is polyvinyl alcohol embolic microcapsules, and the reactant raw materials of the polyvinyl alcohol embolic microcapsules include: 1 part by weight of polyvinyl alcohol, 0.5-7.5 parts by weight of X-ray-opaque substances, 0.2-5 parts by weight of magnetic resonance imaging substances, 1-5.5 parts by weight of inorganic salts, 4-15 parts by weight of cross-linking agents, 0.9-13.1 parts by weight of catalysts and 0-3 parts by weight of drugs;

Preferably, the embolic material composition is polyvinyl alcohol embolic microcapsules, and the reactant raw materials of the polyvinyl alcohol embolic microcapsules include: 1 part by weight of polyvinyl alcohol, 1-6.5 parts by weight of X-ray opaque substances, 0.7- 4.5 parts by weight of magnetic resonance imaging substances, 2.5-3.5 parts by weight of inorganic salts, 6-11 parts by weight of crosslinking agents, 5.8-13.1 parts by weight of catalysts and 0.5-1.5 parts by weight of drugs;

Preferably, the embolic material composition is polyvinyl alcohol embolic microspheres, and the reactant raw materials of the polyvinyl alcohol embolic microspheres include: 1 part by weight of polyvinyl alcohol, 2-8 parts by weight of X-ray-opaque substances and 0.5-4 parts by weight of magnetic resonance imaging material, 0.015-0.31 parts by weight of inorganic salt, 0.6-2.3 parts by weight of crosslinking 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 An immiscible organic solvent and 0-6 parts by weight of medicine;

Preferably, the embolic material composition is polyvinyl alcohol embolic microspheres, and the reactant raw materials of the polyvinyl alcohol embolic microspheres include: 1 part by weight of polyvinyl alcohol, 6-8 parts by weight of X-ray-opaque substances, 1-4 parts by weight of magnetic resonance imaging material, 0.15-0.31 parts by weight of inorganic salt, 0.6-1.2 parts by weight of crosslinking agent, 0.8-1.5 parts by weight of catalyst, 0.6-2 parts by weight of surfactant, 10-50 parts by weight of water An immiscible organic solvent and 2-6 parts by weight of medicine.

Further, the biocompatible material is gelatin; preferably, the embolic material composition is gelatin embolization microcapsules, and the reactant raw materials of the gelatin embolization microcapsules include: 1 weight part gelatin, 1-9.5 weight parts X-ray-opaque substances, 0.5-5 parts by weight of magnetic resonance imaging materials, 0.3-1.5 parts by weight of cross-linking agents and 0-4.5 parts by weight of drugs;

Preferably, the embolic material composition is a gelatin embolic microcapsule, and the reactant raw materials of the gelatin embolic microcapsule include: 1 part by weight of gelatin, 2-3.5 parts by weight of X-ray-opaque substances, 0.8-3 parts by weight of magnetic resonance imaging substance, 1.1-1.5 parts by weight of cross-linking agent and 0.5-4.5 parts by weight of drug;

Preferably, the embolic material composition is gelatin embolic microspheres, and the reactant raw materials of the gelatin embolic microspheres include: 1 part by weight of gelatin, 0.8-8 parts by weight of X-ray-opaque substances, 0.3-3.5 parts by weight of magnetic Resonance imaging material, 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 embolic material composition is gelatin embolic microspheres, and the reactant raw materials of the gelatin embolic microspheres include: 1 part by weight of gelatin, 0.8-2.2 parts by weight of X-ray-opaque substances, 0.5-3.5 parts by weight of magnetic Resonance imaging material, 0.7-3.7 parts by weight of cross-linking agent, 0.39-1.87 parts by weight of surfactant, 10-40 parts by weight of organic solvent immiscible with water and 0.5-4.5 parts by weight of medicine.

Further, the biocompatible material is a mixture of chitosan and sodium carboxymethylcellulose;

The embolic material composition is a chitosan-carboxymethylcellulose embolization microcapsule, and the reactant raw material of the chitosan-carboxymethylcellulose embolization microcapsule comprises: 1 part by weight of a biocompatible material, 4 - 10 parts by weight of an X-ray-opaque oily liquid, 0.5-5 parts by weight of a magnetic resonance imaging substance, 0.2-0.8 parts by weight of a cross-linking agent, and 0-4.5 parts by weight of a drug.

Preferably, the inorganic salt used to prepare polyvinyl alcohol embolization microspheres is selected from one or more of water-soluble sodium salts, potassium salts or ammonium salts; preferably potassium chloride, sodium chloride or ammonium chloride, etc. One or more, more preferably sodium chloride; the inorganic salt used to prepare polyvinyl alcohol embolism microcapsules is selected from one or more of sulfate, phosphate, silicate or acetate, preferably sodium sulfate , one or both of aluminum sulfate, ammonium sulfate, sodium tripolyphosphate, etc., more preferably sodium sulfate;

Preferably, the crosslinking agent is selected from one or more of formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or adipaldehyde; the catalyst is selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid or acetic acid, etc. one or more of

Preferably, the surfactant is selected from one or both of Span-type surfactants or a mixture of Span-type surfactants and Tween-type surfactants, preferably Span 80 or Span 85 one or both of

The embolization microspheres are prepared in a water-immiscible organic solvent selected from mineral oil, vegetable oil, silicone oil, olefin, alcohol, aldehyde, amine, ether, ketone, terpene hydrocarbon, halogen One or more of substituted hydrocarbons, heterocyclic compounds, nitrogen-containing compounds or sulfur-containing compounds, preferably liquid paraffin or cyclohexane;

Preferably, the drug is selected from one or more of antineoplastic drugs, local anesthetic drugs, antipyretic and analgesic anti-inflammatory drugs or antibiotic drugs;

Preferably, the antineoplastic drug is selected from doxorubicin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel , docetaxel, 5-fluorouracil, pingyangmycin, sunitinib, sorafenib, gefitinib, imatinib, vatalanib ( Vatalanib) or its salts, etc.;

Preferably, the local anesthetic is selected from the group consisting of procaine, chloroprocaine, hydroxyprocaine, tetracaine, p-ethoxycaine, tutocaine, methocaine, lidocaine , trimethylcaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, dibucaine, dyclonine, manacaine, quinicaine, phenacaine or its salts, etc. one or more of

Preferably, the antipyretic, analgesic and anti-inflammatory drugs are selected from aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, salicylate, ibuprofen, indole Maximin, flurbiprofen, phenoxyibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, acetaminophen, diclofenac, fenprofen, ketoprofen, ketoprofen One or more of tetraclofenamic acid, sulindac or tolmetin;

Preferably, the antibiotic drug is selected from β-lactam antibiotics (such as penicillin, oxacillin sodium, ampicillin sodium, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid or bactam), tetracyclines (such as oxytetracycline, tetracycline, or demeclocycline), aminoglycosides (streptomycin, kanamycin A, gentamicin, tobramycin, sisomicin , amikacin, dibekacin, isopamicin, ribomycin, kanamycin B, neomycin B, or paromomycin), macrolide antibiotics (such as erythromycin, erythromycin, clarithromycin, or azithromycin) or one or more of other antibiotics (such as chloramphenicol, cyclosporine, or lincomycin) or their salts.

The embolic material composition of the present invention can be stored in physiological saline or phosphate buffer, or freeze-dried.

The method of using the embolic material composition of the present invention is the same as that of common embolic agents.

The present invention further provides a preparation method of the above embolic material composition, the preparation method comprising the following steps:

Step a: preparing the biocompatible material into a solution;

Step b: adding X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the solution of step a; preferably, when the X-ray-opaque substances are oily liquids, the drugs and/or magnetic resonance The imaging material is dispersed in the X-ray-opaque material to obtain a mixed solution, and then the mixed solution is added to the solution in step a;

Step c: Polymerize the biocompatible material by physical chemical method, physical mechanical method or chemical method to obtain an embolism material composition.

Further, the embolic material composition is polyvinyl alcohol embolic microcapsules, and the polyvinyl alcohol embolic microcapsules are prepared by the following method:

Step a1: Weigh the polyvinyl alcohol of formula quantity, prepare the polyvinyl alcohol solution of 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, more preferably 0.025g/ml;

Step b1: adding X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the polyvinyl alcohol solution in step a1, and stirring to obtain a mixed solution;

Step c1: Take the inorganic salt of formula quantity, be mixed with the inorganic salt solution of 0.1-0.4g/ml, preferably 0.21-0.29g/ml, more preferably 0.25g/ml, under this condition, the polyvinyl alcohol solution Cloud point temperature, preferably at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition, add the inorganic salt solution to the mixed solution in step b1, continue to stir and slowly heat up, when the temperature rises to When the cloud point temperature is reached, add a crosslinking agent and a catalyst, and cure at a constant temperature for 15-23 hours, preferably for 21-23 hours, more preferably for 22 hours, and obtain polyvinyl alcohol embolism microcapsules after filtering and washing; or,

The polyvinyl alcohol embolic microcapsules are prepared by the following method:

Step a2: Weigh the polyvinyl alcohol of formula quantity, prepare the polyvinyl alcohol solution of 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, more preferably 0.025g/ml;

Step b2: Take the inorganic salt of formula quantity, prepare the inorganic salt solution of 0.1-0.4g/ml, preferably 0.21-0.29g/ml, more preferably 0.25g/ml, mix the inorganic salt solution with the polyethylene in step a2 Alcohol solution is mixed, then add X-ray opaque material, magnetic resonance imaging material and optional drug, the cloud point temperature is lower than the polyvinyl alcohol solution under this condition, preferably lower than the cloud point temperature of the polyvinyl alcohol solution under this condition Stir at a water bath temperature with a point temperature of 5-15°C to obtain a mixed solution;

Step c2: Continue to stir and slowly heat up. When the temperature rises to the cloud point temperature, add a crosslinking agent and a catalyst, and cure at a constant temperature for 15-23 hours, preferably 21-23 hours, more preferably 22 hours, and obtain polyethylene after filtration and washing Alcohol embolization microcapsules.

Further, the embolic material composition is polyvinyl alcohol embolic microspheres, and the polyvinyl alcohol embolic microspheres are prepared by the following method:

Step a3: Weigh the formulated amount of inorganic salt, prepare an aqueous inorganic salt solution of 0.0045-0.025g/ml, preferably 0.017-0.025g/ml, more preferably 0.02g/ml, and dissolve the formulated amount of polyvinyl alcohol in the inorganic salt In the aqueous solution, the polyvinyl alcohol concentration obtained is 0.08-0.3g/ml, preferably 0.21-0.3g/ml, more preferably 0.21g/ml solution;

Step b3: adding X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the solution in step a3 at room temperature, and stirring to obtain a mixed solution;

Step c3: Pour the mixed solution made in step b3 into a water-immiscible organic solvent containing a surfactant to form an emulsion, then add a crosslinking agent and a catalyst at a stirring speed of 300-1500rpm and 30-65 Cure at ℃ water bath temperature for 2-23h, preferably at 550-650rpm stirring speed and 30-45℃ water bath temperature for 3.5-6h, more preferably at 600rpm stirring speed and 30℃ water bath temperature for 4h, after filtering and washing Obtain polyvinyl alcohol embolization microsphere; Or add cross-linking agent and catalyst in the mixed solution that step b3 is made, stir and pour in the water-immiscible organic solvent containing surfactant, make emulsion, then in 300-1500rpm stirring speed and 30-65°C water bath temperature for 2-23h, preferably 550-650rpm stirring speed and 30-45°C water bath temperature for 3.5-6h, more preferably 600rpm stirring speed and 30°C It was cured for 4 hours at the water bath temperature, filtered and washed to obtain polyvinyl alcohol embolism microspheres.

Further, the embolic material composition is gelatin embolic microcapsules or gelatin embolic microspheres; the gelatin embolic microcapsules are prepared by the following method:

Step a4: Weigh the gelatin in the formula amount, swell the gelatin with distilled water to make a gelatin solution of 0.005-0.1g/ml, preferably 0.005-0.035g/ml, more preferably 0.035g/ml;

Step b4: Under the condition of 40-60°C, preferably 53°C water bath, add X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the gelatin solution in step a4, stir to obtain a mixed solution; then adjust the mixing The pH value of the solution is 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. After the microcapsules are formed, distilled water is added to dilute to obtain a microcapsule suspension;

Step c4: The microcapsule suspension obtained in step b4 is solidified by adding a crosslinking agent in an ice-water bath for 0.5-24 hours, preferably 70 minutes or 15 hours, and then filtering and washing to obtain gelatin plug microcapsules;

When the cross-linking agent is formaldehyde, the above step c4 specifically includes: adding formaldehyde to the microcapsule suspension obtained in step b4 in an ice-water bath and stirring for 2-15min, preferably 10min, adjusting the pH value to 8-9, preferably dropwise Adjust the pH value to 8-9 with 0.1 g/ml sodium hydroxide solution, solidify for 0.5-24 hours, preferably 15 hours, filter and wash to obtain gelatin embolism microcapsules.

The gelatin embolization microspheres are prepared by the following method:

Step a5: Weigh the gelatin of the formula amount, swell the gelatin with distilled water to make a gelatin solution of 0.08-0.35g/ml, preferably 0.15-0.30g/ml, more preferably 0.28g/ml;

Step b5: Add X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the gelatin solution in step a5 under the condition of 35-63°C, preferably 53°C, in a water bath, and stir to obtain a mixed solution;

Step c5: Pour the mixture prepared in step b5 into a water-immiscible organic solvent containing a surfactant to form an emulsion, transfer the emulsion to an ice-water bath and stir for 5-60 minutes, preferably 30 minutes, and add a crosslinking agent , solidified for 0.5-24h, preferably 70min or 15h, filtered and washed to obtain gelatin embolism microspheres.

When the cross-linking agent is formaldehyde, the above-mentioned step c5 specifically includes: pouring the mixed solution prepared in step b5 into a water-immiscible organic solvent containing a surfactant to form an emulsion, and transferring the emulsion to an ice-water bath for stirring 5-60min, preferably 30min, add formaldehyde and stir for 2-15min, preferably 10min, adjust the pH value to 8-9, preferably dropwise add 0.1g/ml sodium hydroxide solution to adjust the pH value to 8-9, solidify for 0.5-24h, preferably After 15 hours, gelatin embolization microspheres were obtained after filtration and washing.

Further, the embolic material composition is chitosan-carboxymethylcellulose embolic microcapsules, and the chitosan-carboxymethylcellulose embolic sodium microcapsules are prepared by the following method:

Step a6: Take the chitosan of formula quantity, prepare the acetic acid solution containing 0.006-0.009g/ml chitosan, weigh the sodium carboxymethyl cellulose of formula quantity, prepare the carboxymethyl cellulose of 0.02-0.056g/ml Cellulose sodium aqueous solution, the acetic acid solution of chitosan is mixed with carboxymethyl cellulose sodium aqueous solution to obtain mixed solution;

Step b6: Add X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the mixed solution in step a6, stir to make a mixed solution, adjust the pH value of the mixed solution to 5.5-6.5, preferably 0.1 g/ml sodium hydroxide solution to adjust the pH value of the emulsion to 5.5-6.5, react for 5-60min, preferably 20min;

Step c6: Put the reaction solution in step b6 in an ice-water bath, add a crosslinking agent, crosslink and solidify for 0.5-2h, preferably 1h, filter and wash to obtain chitosan-carboxymethylcellulose embolism microcapsules.

The present invention further provides the above-mentioned embolic material composition for the treatment of tumors, such as liver cancer, colorectal cancer liver metastases, kidney cancer, lung cancer, prostate cancer, ovarian cancer, uterine fibroids or malignant breast tumors, or vascular malformations or for Use in drugs such as hemostasis.

Compared with the prior art, the embolic material composition of the present invention has at least the following advantages:

1. The present invention prepares an embolic material composition with dual imaging capabilities of X-rays and magnetic resonance by using biocompatible materials to wrap X-ray-opaque substances and magnetic resonance imaging substances, so that the embolic material composition has good biocompatibility and can be directly detected by X-ray imaging equipment and MRI at the same time. Compared with pure X-ray or MRI imaging embolic agents, the embolic material composition of the present invention is not limited to monitoring with a single device, and X-ray imaging equipment (such as CT, DSA) or MRI for monitoring, it is convenient to check the effect of embolization during and after embolization, and it is more convenient to use.

2. Compared with non-developing embolic agents, the embolic material composition of the present invention is convenient for doctors to monitor the position of the embolic agent and the end point of embolization during and after embolization, improving the efficacy and safety of treatment.

3. Drugs can be loaded into the embolic material composition of the present invention, and the drug-loaded embolic material composition can be embolized to a specific site under the monitoring of X-ray imaging equipment (such as CT) or MRI, so as to better realize the Targeted delivery of drugs; slow release of drugs from microparticles can be achieved, and high drug concentration can be maintained in the embolized area for a long time. Compared with infusion therapy, it can reduce the systemic side effects of drugs and help improve the curative effect of embolization therapy .

4. The present invention adopts biocompatible materials, X-ray-opaque substances and magnetic resonance imaging substances to prepare embolic material compositions. The preparation process is simple, the cost is low, and it is suitable for large-scale industrial production.

Description of drawings

Below, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:

Fig. 1 is the optical micrograph of the polyvinyl alcohol embolic microsphere that the embodiment of the present invention 5 prepares;

Fig. 2 is the in vitro CT detection image of the polyvinyl alcohol embolic microspheres prepared in Example 5 of the present invention;

3 is an in vitro MRI detection image of polyvinyl alcohol embolization microspheres prepared in Example 5 of the present invention;

Fig. 4 is the CT image of the subcutaneous mouse subcutaneous polyvinyl alcohol embolization microspheres prepared in Example 5 of the present invention;

Fig. 5 is the MRI image of the subcutaneous mouse subcutaneous polyvinyl alcohol embolization microspheres prepared in Example 5 of the present invention;

Fig. 6 is the in vitro drug release curve of paclitaxel-loaded polyvinyl alcohol embolization microspheres prepared in Example 8 of the present invention.

Detailed ways

The present invention will be described below with reference to specific examples. Those skilled in the art can understand that these examples are only used to illustrate the present invention and do not limit the scope of the present invention in any way.

The experimental methods in the following examples are conventional methods unless otherwise specified. The pharmaceutical raw materials, reagents, materials, etc. used in the following examples are all commercially available products unless otherwise specified.

The preparation of embodiment 1 polyvinyl alcohol embolism microcapsule

1) Weigh 1g of polyvinyl alcohol and prepare a 0.008g/ml polyvinyl alcohol solution;

2) Mix 6.5g iodized oil, 5g iron ferric oxide nanoparticles and 1.5g paclitaxel evenly, then add them to the polyvinyl alcohol solution obtained in step 1), and stir to make an oil-in-water (o/w) emulsion;

3) Weigh 3.0g of sodium sulfate and prepare a 0.21g/ml sodium sulfate solution, and add the sodium sulfate solution to step 2 at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition ) to the obtained emulsion, continue to stir and slowly raise the temperature, when the temperature rises to the cloud point temperature, add 11g formaldehyde and 5.8g sulfuric acid, solidify at constant temperature for 20h, let stand to separate layers, pour out the supernatant, filter and wash to get Polyvinyl alcohol embolization microcapsules.

The preparation of embodiment 2 polyvinyl alcohol embolic microspheres

1) Weigh 0.31g of sodium chloride, prepare a 0.025g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.08g/ml;

2) Disperse 2g of ferric oxide nanoparticles and 6g of paclitaxel in 8g of iodized oil to obtain a mixed solution, then add the mixed solution to the polyvinyl alcohol solution in step 1) at room temperature and stir to make a water-in-packet Oil (o/w) type emulsion;

3) Pour the emulsion prepared in step 2) into 60g of liquid paraffin containing 2.5g of Span 85 to make an oil-in-water-in-oil type (o/w/o) double emulsion, and then add 0.6g of glutaraldehyde and 0.5 g of sulfuric acid was solidified for 2 hours at a stirring speed of 300 rpm and a water bath temperature of 35° C., filtered and washed to obtain polyvinyl alcohol embolization microspheres.

The preparation of embodiment 3 gelatin embolization microcapsules

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.03g/ml gelatin solution;

2) Disperse 0.5g of sorafenib and 3g of ferric oxide in 3.5g of iodized oil to obtain a mixed solution, and add the obtained mixed solution to the gelatin solution in step 1) in a water bath at 40°C, Stir to make an oil-in-water (o/w) emulsion, then add dropwise 0.1g/ml acetic acid solution to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, add distilled water to dilute, and obtain microcapsules Capsule suspension;

3) Add 1.5g of formaldehyde to the microcapsule suspension obtained in step 2) and stir for 2 minutes in an ice-water bath, add dropwise 0.1g/ml sodium hydroxide solution, adjust the pH value to 8-9, solidify for 15 hours, and let stand to separate layer, decanting the supernatant, filtering and washing to obtain gelatin embolized microcapsules.

The preparation of embodiment 4 polyvinyl alcohol embolic microspheres

1) Weigh 0.15g of sodium chloride, prepare a 0.018g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and prepare a solution with a polyvinyl alcohol concentration of 0.12g/ml;

2) Disperse 4g of ferric oxide nanoparticles and 1.5g of sorafenib in 6g of iodophenyl ester to obtain a mixed solution, then add the mixed solution to the polyvinyl alcohol solution in step 1) at room temperature, and stir , made into oil-in-water (o/w) emulsion;

3) Pour the emulsion prepared in step 2) into 17g castor oil containing 0.4g Span 85 to make an oil-in-water-in-oil (o/w/o) type double emulsion, then add 0.8g formaldehyde and 0.6g Sulfuric acid was solidified at a stirring speed of 1500 rpm and a water bath temperature of 45° C. for 7 hours, filtered and washed to obtain polyvinyl alcohol embolism microspheres.

The preparation of embodiment 5 polyvinyl alcohol embolic microspheres

1) Weigh 0.17g of sodium chloride, prepare a 0.025g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.15g/ml;

2) At room temperature, mix 7g iodized oil and 1.7g iron ferric oxide nanoparticles evenly, then add them to the polyvinyl alcohol solution in step 1), and stir to make an oil-in-water (o/w) emulsion;

3) Add 0.9g of formaldehyde and 0.8g of sulfuric acid to the emulsion prepared in step 2), stir it quickly and pour it into 50g of liquid paraffin containing 2g of Span 80 to make oil-in-water-in-oil (o/w/o ) type double emulsion, solidified at a stirring speed of 750 rpm and a water bath temperature of 30°C for 4 hours, filtered and washed to obtain polyvinyl alcohol embolism microspheres.

The morphology of the above-prepared polyvinyl alcohol embolization microspheres under an optical microscope is shown in FIG. 1 . It can be seen from Figure 1 that the prepared polyvinyl alcohol embolic microspheres are regular spherical, with good dispersion and no bonding and agglomeration.

Embodiment 6 Preparation of gelatin embolization microspheres

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.3g/ml gelatin solution;

2) Disperse 0.5g MnFe ₂ O ₄ in 1.2g iodized oil in a water bath at 53°C to make a mixed solution, add the mixed solution to the gelatin solution in step 1), and stir to make an oil-in-water ( o/w) type emulsion;

3) Pour the emulsion prepared in step 2) into 10g cyclohexane containing 0.39g Span 80 to make an oil-in-water-in-oil (o/w/o) type emulsion, transfer the emulsion to an ice-water bath to continue Stir for 30 minutes, add 0.2g formaldehyde and stir for 2 minutes, add 0.1g/ml sodium hydroxide solution dropwise, adjust the pH value to 8-9, solidify for 10 hours, let stand to separate layers, pour out the supernatant, filter and wash to obtain a gelatin plug Microspheres.

The preparation of embodiment 7 chitosan-carboxymethyl cellulose embolism microcapsules

1) Weigh 0.1g chitosan to make an acetic acid solution containing 0.006g/ml chitosan, weigh 0.9g sodium carboxymethyl cellulose to make a 0.056g/ml sodium carboxymethyl cellulose aqueous solution, The acetic acid solution of chitosan is mixed with the sodium carboxymethyl cellulose aqueous solution to obtain a mixed solution;

2) Mix 4g iodized oil and 0.5g ferric oxide nanoparticles evenly and add them to the mixed solution in step 1), stir magnetically to make an oil-in-water (o/w) emulsion; use 0.1g/ml hydrogen The sodium oxide solution adjusts the pH value of the emulsion to 5.5-6.5, and reacts for 5 minutes;

3) Put the reaction solution in step 2) in an ice-water bath, add 0.2g of glutaraldehyde, cross-link and solidify for 0.5h, let it stand for layers, pour out the supernatant, filter and wash to obtain chitosan-carboxylate Methylcellulose Embolization Microcapsules.

The preparation of embodiment 8 polyvinyl alcohol embolic microspheres

1) Weigh 0.015g sodium chloride, prepare 0.0045g/ml sodium chloride aqueous solution, dissolve 1g polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.3g/ml;

2) Disperse 1.2g paclitaxel and 0.8g iron ferric oxide nanoparticles in 2.2g iodized oil at room temperature to make a mixed solution, add the mixed solution to the polyvinyl alcohol solution in step 1) to make oil-in-water (o/w) type emulsion;

3) Add 2.3g of glutaraldehyde and 1.8g of sulfuric acid to the emulsion prepared in step 2), mix well, pour into 5g of liquid paraffin containing 0.1g of Span 85, and solidify at 550rpm and 55°C water bath temperature for 16h, After filtering and washing, the polyvinyl alcohol embolization microspheres are obtained.

The preparation of embodiment 9 gelatin embolization microcapsules

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.1g/ml gelatin solution;

2) Disperse 0.8g gamma ferric oxide in 1g iodized oil in a water bath at 50°C to make a mixed solution, add the mixed solution to the gelatin solution in step 1), and stir to make oil-in-water ( o/w) type emulsion; then add 0.1g/ml acetic acid solution dropwise to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, dilute with distilled water to obtain a microcapsule suspension;

3) The microcapsule suspension obtained in step 2) was solidified by adding 0.3 g of glutaraldehyde in an ice-water bath for 70 minutes, left to stand for stratification, poured out the supernatant, filtered and washed to obtain gelatin embolism microcapsules.

The preparation of embodiment 10 polyvinyl alcohol embolization microcapsules

1) Weigh 1g of polyvinyl alcohol and prepare a 0.0035g/ml polyvinyl alcohol solution;

2) Mix 7g of iodized oil, 0.5g of tantalum powder, 4.5g of ferric oxide nanoparticles and 3g of paclitaxel, and then add them to the polyvinyl alcohol solution obtained in step 1), and stir to make oil-in-water (o/w ) type emulsion;

3) Weigh 5.5g of sodium sulfate and prepare 0.1g/ml sodium sulfate solution, and add the sodium sulfate solution to step 2 at a water bath temperature lower than the cloud point temperature of the polyvinyl alcohol solution at 5-15°C under this condition ) to the obtained emulsion, continue to stir and slowly heat up, when the temperature rises to the cloud point temperature, add 15g of formaldehyde and 13.1g of sulfuric acid, solidify at a constant temperature for 23h, let stand to separate layers, pour out the supernatant, filter and wash to get Polyvinyl alcohol embolization microcapsules.

Example 11 Preparation of Polyvinyl Alcohol Embolization Microcapsules

1) Weigh 1g of polyvinyl alcohol and prepare a 0.025g/ml polyvinyl alcohol solution;

2) Weigh 2.5g of sodium sulfate and prepare a 0.29g/ml sodium sulfate solution, mix the sodium sulfate solution with the polyvinyl alcohol solution in step 1), then add 2.1g of iodized oil and 1.7g of four Ferric oxide nanoparticles, stirred at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition, to obtain an oil-in-water (o/w) emulsion;

3) Continue to stir and raise the temperature slowly. When the temperature rises to the cloud point temperature, add 8g of formaldehyde and 1.8g of hydrochloric acid, solidify at constant temperature for 23 hours, let it stand for stratification, pour out the supernatant, filter and wash to obtain polyvinyl alcohol embolism Microcapsules.

Example 12 Preparation of Polyvinyl Alcohol Embolization Microcapsules

1) Weigh 1g of polyvinyl alcohol and prepare a 0.015g/ml polyvinyl alcohol solution;

2) Weigh 3.5g of sodium sulfate and prepare a 0.262g/ml sodium sulfate solution, mix the sodium sulfate solution with the polyvinyl alcohol solution in step 1), then add 3.5g of iodized oil and 2.4g of four Ferric oxide nanoparticles and 1.1g of doxorubicin are stirred at a water bath temperature lower than the cloud point temperature of polyvinyl alcohol solution of 5-15°C under the conditions to obtain an oil-in-water (o/w) emulsion;

3) Continue to stir and raise the temperature slowly. When the temperature rises to the cloud point temperature, add 10g of formaldehyde and 11g of hydrochloric acid, solidify at constant temperature for 20h, let stand for stratification, pour out the supernatant, filter and wash to obtain polyvinyl alcohol embolism bag.

Example 13 Preparation of Polyvinyl Alcohol Embolization Microcapsules

1) Weigh 1g of polyvinyl alcohol and prepare a 0.05g/ml polyvinyl alcohol solution;

2) Disperse 0.2g of iron ferric oxide nanoparticles in 0.5g of iodized oil to obtain a mixed solution, then add the mixed solution to the polyvinyl alcohol solution obtained in step 1), and stir to make an oil-in-water (o/ w) type emulsion;

3) Weigh 1g of sodium tripolyphosphate and make it into a 0.25g/ml sodium tripolyphosphate solution. Dissolve sodium tripolyphosphate at a water bath temperature lower than the cloud point temperature of the polyvinyl alcohol solution at 5-15°C under this condition. Add the solution into the emulsion obtained in step 2), continue to stir and slowly raise the temperature, when the temperature rises to the cloud point temperature, add 4g of formaldehyde and 0.9g of sulfuric acid, solidify at a constant temperature for 15h, let stand to separate layers, and pour out the supernatant, After filtering and washing, the polyvinyl alcohol embolism microcapsules are obtained.

Embodiment 14 Preparation of polyvinyl alcohol embolization microspheres

1) Weigh 0.043g of sodium chloride, prepare a 0.01g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.23g/ml;

2) Mix 2.8g iodized oil, 1.2g iron ferric oxide nanoparticles and 1.5g paclitaxel at room temperature and add them to the polyvinyl alcohol solution in step 1), stir to make oil-in-water (o/w ) type emulsion;

3) Add 1.2g of glutaraldehyde and 1.1g of sulfuric acid to the emulsion prepared in step 2), mix well, pour into 11g of liquid paraffin containing 0.4g of Span 85, and solidify at 600rpm and 65°C water bath temperature for 23h, After filtering and washing, the polyvinyl alcohol embolization microspheres are obtained.

The preparation of embodiment 15 gelatin embolization microcapsules

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.035g/ml gelatin solution;

2) Under the condition of 60°C water bath, mix 1.5g iodized oil, 0.5g tantalum powder, 0.5g ferric oxide nanoparticles and 0.5g sorafenib evenly, then add them to the gelatin solution in step 1), and stir , to make a mixed solution, then dropwise add 0.1g/ml acetic acid solution to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, add distilled water to dilute to obtain a microcapsule suspension;

3) Add 0.1g of formaldehyde to the microcapsule suspension obtained in step 2) and stir for 15 minutes in an ice-water bath, add 0.1g/ml sodium hydroxide solution dropwise, adjust the pH value to 8-9, solidify for 10 hours, and let stand to separate layer, decanting the supernatant, filtering and washing to obtain gelatin embolized microcapsules.

The preparation of embodiment 16 gelatin embolization microspheres

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.28g/ml gelatin solution;

2) Under the condition of water bath at 45°C, mix 2g iodized oil, 0.2g tantalum powder, 1g ferric oxide nanoparticles and 1g paclitaxel evenly, then add them to the gelatin solution in step 1), and stir to make a mixed solution;

3) Pour the emulsion prepared in step 2) into 25g of liquid paraffin containing 0.51g of Span 80 to make an oil-in-water (w/o) emulsion. Transfer the emulsion to an ice-water bath and continue stirring for 5 minutes. Add 0.7 The g glutaraldehyde was solidified for 70 min, left to separate layers, poured out the supernatant, filtered and washed to obtain gelatin embolism microspheres.

The preparation of embodiment 17 gelatin embolization microspheres

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.08g/ml gelatin solution;

2) Under the condition of water bath at 63°C, mix 8g iodized oil, 3.5g iron ferric oxide nanoparticles and 4.5g paclitaxel evenly, then add them to the gelatin solution in step 1), and stir to make oil-in-water (o/ w) type emulsion;

3) Pour the emulsion prepared in step 2) into 50g of liquid paraffin containing 3.13g of Span 80 to make an oil-in-water-in-oil (o/w/o) type emulsion, transfer the emulsion to an ice-water bath and continue stirring 60min, add 3.7g formaldehyde and stir for 10min, add dropwise 0.1g/ml sodium hydroxide solution, adjust the pH value to 8-9, solidify for 15h, let stand to separate layers, pour out the supernatant, filter and wash to obtain gelatin plug microspheres ball.

The preparation of embodiment 18 gelatin embolization microspheres

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.35g/ml gelatin solution;

2) In a water bath at 35°C, mix 0.8g lipiodol, 0.3g DyFe ₂ O ₄ nanoparticles and 0.5g sorafenib evenly, add them to the gelatin solution in step 1), stir, and make a water bag Oil (o/w) type emulsion;

3) Pour the emulsion prepared in step 2) into 5g of liquid paraffin containing 0.1g of Span 80 to make an oil-in-water-in-oil (o/w/o) type emulsion, transfer the emulsion to an ice-water bath and continue stirring 20min, add 0.1g formaldehyde and stir for 15min, add dropwise 0.1g/ml sodium hydroxide solution, adjust the pH value to 8-9, solidify for 24h, let stand to separate layers, pour out the supernatant, filter and wash to obtain gelatin plug microspheres ball.

The preparation of embodiment 19 chitosan-carboxymethyl cellulose embolism microcapsules

1) Weigh 0.5g chitosan to make an acetic acid solution containing 0.009g/ml chitosan, weigh 0.5g sodium carboxymethyl cellulose to make a 0.035g/ml sodium carboxymethyl cellulose aqueous solution, The acetic acid solution of chitosan is mixed with the sodium carboxymethyl cellulose aqueous solution to obtain a mixed solution;

2) Mix 5g of iodized oil, 2.5g of ferric oxide nanoparticles and 2.4g of cisplatin evenly, then add to the mixed solution in step 1), and stir magnetically to make an oil-in-water (o/w) emulsion; 0.1g/ml sodium hydroxide solution to adjust the pH value of the emulsion to 5.5-6.5, and react for 20 minutes;

3) Put the reaction solution in step 2) in an ice-water bath, add 0.8g of glutaraldehyde, cross-link and solidify for 2 hours, let stand to separate layers, pour out the supernatant, filter and wash to obtain chitosan-carboxymethyl Cellulose-based embolism microcapsules.

Embodiment 20 Preparation of polyvinyl alcohol embolism microcapsules

1) Weigh 1g of polyvinyl alcohol and prepare a 0.04g/ml polyvinyl alcohol solution;

2) Mix 1g iodized oil, 0.7g iron ferric oxide nanoparticles and 0.2g docetaxel evenly, then add to the polyvinyl alcohol solution obtained in step 1), stir to make oil-in-water (o/w) type Emulsion;

3) Weigh 2g of aluminum sulfate and prepare it into a 0.4g/ml aluminum sulfate solution, and add the aluminum sulfate solution to step 2 at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition) In the obtained emulsion, continue to stir and slowly heat up. When the temperature rises to the cloud point temperature, add 6g of formaldehyde and 9.5g of sulfuric acid, solidify at a constant temperature for 21h, leave to separate layers, pour out the supernatant, filter and wash to obtain poly Vinyl alcohol embolization microcapsules.

Example 21 Preparation of Polyvinyl Alcohol Embolization Microcapsules

1) Weigh 1g of polyvinyl alcohol and prepare a 0.035g/ml polyvinyl alcohol solution;

2) Mix 1.5g iodized oil, 1g iron ferric oxide nanoparticles and 0.5g sorafenib evenly, then add to the polyvinyl alcohol solution obtained in step 1), and stir to make oil-in-water (o/w) type emulsion;

3) Weigh 1g of ammonium sulfate and prepare ammonium sulfate solution of 0.175g/ml, and add the ammonium sulfate solution to step 2 at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition) In the obtained emulsion, continue to stir and slowly raise the temperature. When the temperature rises to the cloud point temperature, add 8g of formaldehyde and 3.1g of sulfuric acid, and solidify at a constant temperature for 22h. Let stand to separate layers, pour out the supernatant, filter and wash to obtain poly Vinyl alcohol embolization microcapsules.

Example 22 Preparation of Polyvinyl Alcohol Embolization Microspheres

1) Weigh 0.081g of sodium chloride, prepare a 0.017g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.21g/ml;

2) Mix 3g of iodized oil, 1g of ferric oxide nanoparticles and 2g of paclitaxel at room temperature, then add them to the polyvinyl alcohol solution in step 1), and stir to make an oil-in-water (o/w) emulsion ;

3) Pour the emulsion prepared in step 2) into 14g cyclohexane containing 0.6g Span 85 to make an oil-in-water-in-oil type (o/w/o) double emulsion, and then add 1.1g glutaraldehyde and 0.9 g of sulfuric acid, solidified at a stirring speed of 650 rpm and a water bath temperature of 40° C. for 6 h, filtered and washed to obtain polyvinyl alcohol embolism microspheres.

Example 23 Preparation of Polyvinyl Alcohol Embolization Microspheres

1) Weigh 0.074g of sodium chloride, prepare a 0.02g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.27g/ml;

2) Mix 2g of iodized oil, 0.5g of ferric oxide nanoparticles and 1g of paclitaxel at room temperature and add them to the polyvinyl alcohol solution in step 1), stir to make an oil-in-water (o/w) type Emulsion;

3) Pour the emulsion prepared in step 2) into 10g of liquid paraffin containing 0.7g of Span 85 to make an oil-in-water-in-oil type (o/w/o) double emulsion, and then add 1.4g of glutaraldehyde and 1.5 g of sulfuric acid was cured for 3.5 hours at a stirring speed of 900 rpm and a water bath temperature of 45° C., filtered and washed to obtain polyvinyl alcohol embolism microspheres.

The preparation of embodiment 24 gelatin embolization microcapsules

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.025g/ml gelatin solution;

2) Under the condition of water bath at 46°C, mix 2.5g iodized oil, 1g iron ferric oxide nanoparticles and 1.5g sorafenib evenly, then add them to the gelatin solution in step 1), and stir to make oil-in-water (o/w) type emulsion, then add 0.1g/ml acetic acid solution dropwise to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, dilute with distilled water to obtain a microcapsule suspension;

3) Add 1.1g of formaldehyde to the microcapsule suspension obtained in step 2) and stir for 10 minutes in an ice-water bath, add dropwise 0.1g/ml sodium hydroxide solution, adjust the pH value to 8-9, solidify for 24 hours, and let stand to separate layer, decanting the supernatant, filtering and washing to obtain gelatin embolized microcapsules.

Embodiment 25 Preparation of gelatin embolization microcapsules

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.005g/ml gelatin solution;

2) In a water bath at 53°C, mix 9.5g iodized oil, 5g ferric oxide nanoparticles and 4.5g sorafenib evenly and add them to the gelatin solution in step 1), stir to make oil-in-water (o/w) type emulsion, then add 0.1g/ml acetic acid solution dropwise to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, dilute with distilled water to obtain a microcapsule suspension;

3) The microcapsule suspension obtained in step 2) was solidified by adding 1.3 g of glutaraldehyde in an ice-water bath for 0.5 h, standing for stratification, decanting the supernatant, filtering and washing to obtain gelatin embolism microcapsules.

Embodiment 26 Preparation of gelatin embolization microspheres

1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.15g/ml gelatin solution;

2) Under the condition of 60°C water bath, mix evenly mixed 1.6g iodized oil, 0.7g iron ferric oxide nanoparticles and 0.7g sorafenib and add them into the gelatin solution in step 1), stir to prepare into an oil-in-water (o/w) emulsion;

3) Pour the emulsion prepared in step 2) into 40g of liquid paraffin containing 1.87g of Span 80 to make an oil-in-water-in-oil (o/w/o) emulsion, transfer the emulsion to an ice-water bath and continue stirring After 10 min, 2 g of glutaraldehyde was added, solidified for 0.5 h, allowed to stand for stratification, and the supernatant was poured out, filtered and washed to obtain gelatin embolism microspheres.

Embodiment 27 Preparation of Chitosan-Carboxymethyl Cellulose Embolization Microcapsules

1) Weigh 0.4g chitosan to make an acetic acid solution containing 0.007g/ml chitosan, weigh 0.6g sodium carboxymethyl cellulose to make a 0.02g/ml sodium carboxymethyl cellulose aqueous solution, The acetic acid solution of chitosan is mixed with the sodium carboxymethyl cellulose aqueous solution to obtain a mixed solution;

2) Mix evenly mixed 10g iodized oil, 5g ferric oxide nanoparticles and 4.5g paclitaxel, then add them to the mixed solution in step 1), and stir magnetically to make an oil-in-water (o/w) emulsion; Use 0.1g/ml sodium hydroxide solution to adjust the pH value of the emulsion to 5.5-6.5, and react for 60 minutes;

3) Put the reaction solution in step 2) in an ice-water bath, add 0.5g of glutaraldehyde, cross-link and solidify for 1 hour, let it stand for stratification, pour out the supernatant, filter and wash to obtain chitosan-carboxymethyl Cellulose-based embolism microcapsules.

Preparation of Blank Control Polyvinyl Alcohol Embolization Microspheres

Except not adding iodized oil and iron ferric oxide nanoparticles, the content of each component and the preparation process are the same as in Example 5, and the specific preparation method is as follows:

1) Weigh 0.17g of sodium chloride, prepare a 0.025g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and prepare a solution with a polyvinyl alcohol concentration of 0.15g/ml;

2) Add 0.9g of formaldehyde and 0.8g of sulfuric acid to the polyvinyl alcohol solution in step 1), and mix well to obtain a mixed solution; pour the mixed solution into 50g of liquid paraffin containing 2g of Span 80 to make a water-in-oil type (w/o) The emulsion was solidified at a stirring speed of 750rpm and a water bath temperature of 30°C for 4h, filtered and washed to obtain blank control polyvinyl alcohol microspheres.

Test 1 In vitro CT and MRI detection of embolization microspheres

In vitro CT and MRI detection were performed on the polyvinyl alcohol embolization microspheres prepared in Example 5 and the blank control polyvinyl alcohol embolization microspheres prepared in Comparative Example, respectively. The experimental process is as follows: prepare 2% agar hot solution, pour it into a petri dish, make the liquid surface thickness 1.5cm, after the solution is cooled to form a gel, put the polyvinyl alcohol embolization microspheres and the blank control polyvinyl alcohol embolization microspheres respectively Put it on the surface of agar, pour it into the hot agar solution with a thickness of 1cm again and cool it down, then place the watch glass under CT and 3T MRI for scanning respectively, the detection results under CT and 3T MRI are shown in Figure 2 and Figure 3 respectively Shown: Figure 2 and Figure 3 respectively show the in vitro CT and 3T MRI detection results of polyvinyl alcohol embolization microspheres (right side) and blank control polyvinyl alcohol embolization microspheres (left side). The number of microspheres is 1, 2, 3, 4, 5 respectively), as can be seen from Figure 2 and Figure 3, under CT and 3T MRI, the polyvinyl alcohol magnetic microspheres are clearly visible, while the blank control polyvinyl alcohol Embolization microspheres were largely undetected.

Test 2 CT and MRI detection of embolization microspheres in mice subcutaneous

Sieve out microspheres of 100-300 μm from the polyvinyl alcohol embolization microspheres prepared in Example 5, suspend 2.5ml of microspheres in 20ml of physiological saline containing 1% sodium carboxymethylcellulose, and inject 0.15ml into mice subcutaneously. The mice were scanned under CT and 3T MRI, and the detection results under CT and 3T MRI are shown in Figure 4 and Figure 5, respectively. Figure 4 shows the CT image of the polyvinyl alcohol embolization microspheres subcutaneously in a mouse, and the white arrow marks the injection site. Figure 5 shows the MRI image of polyvinyl alcohol embolization microspheres subcutaneously in mice. In Figure 5, the white bright spots outside the mouse body are vitamin E capsules, and the white arrows indicate the injection site. The results of CT and MRI show that at the mouse subcutaneous injection site Polyvinyl alcohol embolic microspheres can be detected.

Test 3 In vivo embolization of embolization microspheres

The microspheres with a particle size of 100-150 μm were sieved from the polyvinyl alcohol embolization microspheres prepared in Example 5, and sterilized for later use. The 12-hour fasting rabbit was anesthetized and fixed on the operating table, and one side of the carotid artery was separated. Under digital subtraction angiography (DSA), the left renal artery was selectively intubated with a 2.8F catheter and a guide wire through the carotid artery , inject 0.15ml microspheres for renal embolism, DSA examination is performed on the left kidney before and after embolization to determine whether the target vessel is occluded. Postoperatively, CT and MRI were performed, and the results of both CT and MRI showed that the position of the microspheres was consistent with the results of DSA.

Test 4 Drug release experiment of drug-loaded embolic microspheres

The in vitro release of the paclitaxel-loaded polyvinyl alcohol embolization microspheres prepared in Example 8 was measured by the T-tube method. The experimental process is as follows: add 200ml of pH7.4 phosphate buffer into the T-tube as the release medium, the fluidity of the buffer is 50ml/min, and the temperature of the water bath is 37°C. Put 1ml of the above-mentioned microspheres at the bottom of the T-shaped tube, take out 5ml of the release medium at 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, and immediately make up isothermal and equal-volume fresh release medium. Determine the absorbance value, and calculate the release amount according to the standard curve. The drug release curve of paclitaxel-loaded polyvinyl alcohol embolization microspheres is shown in Figure 6. It can be seen from Figure 6 that the drug release rate of paclitaxel-loaded polyvinyl alcohol embolization microspheres is faster in the first 4 hours, the cumulative drug release is about 45% at 4 hours, and the cumulative drug release is about 61% at 24 hours.

The above description of the specific embodiments of the present invention does not limit the present invention, and those skilled in the art can make various changes or deformations according to the present invention, as long as they do not depart from the spirit of the present invention, all should belong to the scope of the appended claims of the present invention.

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.