CN103536970B - A kind of embolism materials and its production and use - Google Patents
A kind of embolism materials and its production and use Download PDFInfo
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- CN103536970B CN103536970B CN201310513272.7A CN201310513272A CN103536970B CN 103536970 B CN103536970 B CN 103536970B CN 201310513272 A CN201310513272 A CN 201310513272A CN 103536970 B CN103536970 B CN 103536970B
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- sodium alginate
- embolism materials
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Abstract
The present invention provides a kind of embolism materials and its production and use, this embolism materials is made up of reactant feed, described reactant feed includes: the magnetic metal ion more than sodium alginate of 1 weight portion and 0.1 weight portion, and wherein, sodium alginate forms coordination compound with magnetic metal ion. The embolism materials of the present invention makes doctor in Embolization and the postoperative MRI that can pass through directly monitors suppository present position, improves the efficacy and saferry of embolotherapy.
Description
Technical field
The invention belongs to interventional medical arts, relate to a kind of embolism materials and its production and use.
Background technology
Interventional therapy is 21st century to develop one of the most rapid subject. Run neck and neck with medical treatment and surgical intervention at present, become the third therapy system.
Embolotherapy is the important component part of interventional therapy, belongs to invasive treatment. Embolotherapy is under the guiding of medical imaging device, and by precision instruments such as special seal wire, conduits, suppository is introduced human body, artificially occluding vascular and the local treatment that carries out. Embolization therapy all has good curative effect in treatment malignant tumor, hysteromyoma, hemangioma, vascular malformation and hemostasis etc., has become as the alternative medicine of partial surgical treatment.
Embolism materials conventional clinically at present mainly has gelatine microsphere/embolism agent of granule, polyvinyl alcohol microballoon/particle embolic agent and Alginate microparticles suppository etc. These embolism materials all can not be directly detected by existing Clinical detection means, and therefore, doctor is difficult by image documentation equipment and directly monitors embolism materials location with postoperative in Embolization. In practical application, doctor is by digital subtraction angiography (DigitalSubtractionAngiography, DSA), according to Iodine contrast medium flowing in the blood vessel, indirectly judges the terminal of suppository location and thromboembolism. There is certain error in this indirect determination methods. A nearest clinical research shows, judge that uterine artery has been had 20% not by complete thromboembolism in the case of complete thromboembolism by DSA, postoperative nuclear magnetic resonance (MagneticResonanceImaging, MRI) checks that the part uterine artery showing these patients still has blood to supply. Therefore, directly being detected by existing Clinical detection means when how to enable embolism materials with postoperative check in Embolization, the efficacy and saferry to improve embolotherapy becomes the problem that this area is urgently to be resolved hurrily.
Summary of the invention
For the problems referred to above, it is an object of the present invention to provide a kind of embolism materials, this embolism materials makes doctor in Embolization and the postoperative MRI that can pass through directly monitors suppository present position, is conducive to improving the efficacy and saferry of embolotherapy.
Another object of the present invention is to the preparation method that a kind of embolism materials is provided.
A further object of the present invention is in that to provide a kind of embolism materials in preparation for treating tumor, such as hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma, malignant breast tumor, or vascular malformation or for the purposes in the medicine of hemostasis etc.
For reaching above-mentioned purpose, the present invention provides a kind of embolism materials, and it is made up of reactant feed, and described reactant feed includes: the magnetic metal ion more than sodium alginate of 1 weight portion and 0.1 weight portion, wherein, sodium alginate forms coordination compound with magnetic metal ion.
Further, described reactant feed farther includes one or more in positively charged macromolecular material, roentgenopaque material, nonmagnetic metal ion, auxiliary agent or medicine; Wherein said auxiliary agent is cross-linking agent or the mixture being made up of cross-linking agent and catalyst;
Preferably, described reactant feed farther includes one or more in following material: more than 0.1-100 weight portion macromolecular material, the roentgenopaque material of 0.01-5 weight portion, 0.01 weight portion nonmagnetic metal ion, 4-500 weight portion auxiliary agent or 0.05-5 weight portion medicine.
Further, described embolism materials adopts emulsion process to prepare, and described reactant feed includes:
Preferably, described reactant feed includes:
Further, described embolism materials adopts dropping preparation method to prepare, and described reactant feed includes:
More than sodium alginate 1 parts by weight of magnetic metal ion 0.1 weight portion
The macromolecular material 0.2-100 weight portion that medicine 0.05-5 weight portion is positively charged
The roentgenopaque material 0.01-5 weight portion of catalyst 1-150 weight portion
More than cross-linking agent 4-350 weight portion nonmagnetic metal ion 0.01 weight portion
Preferably, described reactant feed includes:
Sodium alginate 1 parts by weight of magnetic metal ion 3-1000 weight portion
The macromolecular material 0.3-60 weight portion that medicine 0.1-1 weight portion is positively charged
The roentgenopaque material 0.05-2 weight portion of catalyst 2-100 weight portion
Cross-linking agent 6-250 weight portion nonmagnetic metal ion 0.3-1000 weight portion.
Further, described embolism materials is particle diameter is the microgranule of 1-2000 ��m, it is preferable that particle diameter is the microsphere of 1-2000 ��m.
Further, one or more in described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium plasma;
Preferably, described nonmagnetic metal ion is selected from one or more in calcium, aluminum, barium, lead, cadmium, copper, strontium or zinc plasma;
Preferably, described positively charged macromolecular material is biocompatible polymer material, it is preferable that chitosan or one or both in gelatin;
Preferably, described catalyst is selected from one or more in hydrochloric acid, sulphuric acid, phosphoric acid or acetic acid etc.;
Preferably, described cross-linking agent is selected from one or more in formaldehyde, acetaldehyde, Biformyl, butyraldehyde, boric acid, Borax, glutaraldehyde, hexandial or genipin etc.;
Preferably, described roentgenopaque material is selected from one or more in iodized oil, iofendylate, tantalum powder or barium sulfate;
Preferably, described medicine is selected from one or more in antitumor drug, local anaesthesia medicine, antipyretic-antalgic anti-inflammatory agent thing or antibiotic medicine etc.;
Preferably, described antitumor drug is selected from one or more in amycin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel, Docetaxel, 5-fluorouracil, Bleomycin A5, Sutent (Sunitinib), Sorafenib (Sorafenib), gefitinib (Gefitinib), imatinib (Imatinib), PTK787 (Vatalanib) or its salt etc.;
Preferably, described local anaesthesia medicine selected from procaine, chloroprocaine, hydroxyprocaine, tetracaine, parethoxycaine, on foot hold in the palm in caine, dimethocaine, lignocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, supernatural power caine, quinisocaine, phenacaine or its salt etc. one or more;
Preferably, described antipyretic-antalgic anti-inflammatory agent thing is selected from one or more in aspirin, magnesium salicylate, sodium salicylate, choline magnesium trisalicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, fenoprofen, naproxen, nabumetone, piroxicam, Phenylbutazone, acetaminophen, diclofenac, venlofen, ketone ibuprofen, ketorolac, four clofenamic acides, sulindac or tolmetin etc.;
Preferably, described antibiotic medicine is selected from beta-lactam antibiotic (such as penicillin, oxacillin sodium, ampicillin, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid or sulbactam), tetracycline antibiotics (such as oxytetracycline, tetracycline or demeclocycline), aminoglycoside antibiotics (streptomycin, kanamycin A, gentamycin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribostamycin, bekanamycin, framycetin or paromomycin), macrolide antibiotics (such as erythromycin, Roxithromycin, clarithromycin or azithromycin) or other antibiotic (such as chloromycetin, ciclosporin or lincomycin) or its salt etc. in one or more,
Preferably, one or both in spans surfactant or the mixture that is made up of spans surfactant and Tweens surfactant of described surfactant;
Preferably, described organic solvent is organic solvent immiscible with water; Preferably, described organic solvent is selected from one or more in mineral oil, vegetable oil, silicone oil, alkene, alcohol, aldehyde, amine, ether, ketone, terpene hydrocarbon, halogenated hydrocarbons, heterocycle compound, nitrogen-containing compound or sulfur-containing compound etc., it is preferable that liquid paraffin, isobutyltrimethylmethane. or hexamethylene.
The present invention adopts emulsion process, double emulsion or dropping preparation method etc. by making sodium alginate form coordination compound with magnetic metal ion, makes the embolism materials that can be detected by MRI. The embolism materials of the present invention can add positively charged biocompatible polymer material, with the coordination compound of wrap negative charge, thus stoping or reduce the release of metal ion and regulating the physicochemical property of embolism materials; Also nonmagnetic metal ion can be added in the embolism materials of the present invention, to form coordination compound with sodium alginate, thus regulating the physicochemical property of embolism materials; Also can medicine and/or roentgenopaque material etc. be dispersed in embolism materials, to strengthen the treatment of embolism materials and/or detected character; It can in addition contain add catalyst to make sodium alginate, positively charged macromolecular material and cross-linking agent generation cross-linking reaction with cross-linking agent, to stop or to reduce the release of metal ion and to regulate the physicochemical property of embolism materials.
The preparation method that the present invention further provides above-mentioned embolism materials, described preparation method comprises the following steps:
Step a: sodium alginate is configured to sodium alginate aqueous solution;
Step b: by the sodium alginate soln in step a and the solution reaction containing magnetic metal ion, obtain embolic particles,
Preferably, described preparation method farther includes:
Step c: the embolic particles obtained by step b joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, separates, washs, obtain embolism materials.
Further, described preparation method is dropping preparation method, comprises the following steps:
Step a1: sodium alginate is configured to sodium alginate aqueous solution, adds optional medicine and optional roentgenopaque material forms mixed liquor;
Step b1: under stirring, sodium alginate soln in step a1 or mixed liquor are instilled in the solution containing magnetic metal ion, optionally positively charged macromolecular material and optional nonmagnetic metal ion, after after dripping, stirring more than 60min, preferred 80-120min, separates, washs the microgranule prepared; Preferably, electrostatic drop generator is used the sodium alginate soln in step a1 or mixed liquor to be instilled in the solution containing magnetic metal ion, optionally positively charged macromolecular material and optional nonmagnetic metal ion;
Step c1: the microgranule obtained by step b1 joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, it is preferable that after reacting 8-24h hour, separates, washs, obtain embolism materials,
Preferably, above-mentioned dropping preparation method comprises the following steps:
Step a1: sodium alginate is configured to the sodium alginate aqueous solution of 0.005-0.08g/ml, adds optional medicine and optional roentgenopaque material forms mixed liquor;
Step b1: under stirring, sodium alginate soln in step a1 or mixed liquor are instilled in the solution containing 0.005-0.12g/ml magnetic metal ion, macromolecular material positively charged for optional 0.005-0.12g/ml and optional 0.0005-0.12g/ml nonmagnetic metal ion, after after dripping, stirring more than 60min, preferred 80-120min, separates, washs the microgranule prepared; Preferably, electrostatic drop generator is used the sodium alginate soln in step a1 or mixed liquor to be instilled in the solution containing 0.005-0.12g/ml magnetic metal ion, macromolecular material positively charged for optional 0.005-0.12g/ml and optional 0.0005-0.12g/ml nonmagnetic metal ion;
Step c1: the microgranule obtained by step b1 is added in the mixed solution containing cross-linking agent and optional catalyst, after reaction, it is preferable that after reacting 8-24h hour, separates, washs, obtain embolism materials.
In above-mentioned dropping preparation method, when embolism materials is without positively charged macromolecular material, also can cross-linking agent (and optional catalyst) be joined in the solution containing magnetic metal ion and optional nonmagnetic metal ion, again the sodium alginate aqueous solution in step a1 or mixed liquor are instilled in the mixed solution containing cross-linking agent (and optional catalyst), magnetic metal ion and optional nonmagnetic metal ion, after after dripping, stirring, separation, washing obtain embolic particles.
Further, described preparation method is emulsion process, comprises the following steps:
Step a2: sodium alginate is configured to sodium alginate aqueous solution, add optional medicine and optional roentgenopaque material forms mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant and with in the mixed liquor of the immiscible organic solvent of water, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b2: add in the solution containing magnetic metal ion, optionally positively charged macromolecular material and optional nonmagnetic metal ion in the step a2 Emulsion obtained or emulsion, more than 60min is stirred when low whipping speed is 200-2000rpm, preferred 80-120min, separates, washs the microgranule prepared;
Step c2: the microgranule that step b2 prepares is joined in the mixed solution containing cross-linking agent and optional catalyst, after reaction, it is preferable that after reaction 8-24h, separate, wash, obtain embolism materials;
Preferably, above-mentioned emulsion process comprises the following steps:
Step a2: sodium alginate is configured to the sodium alginate aqueous solution of 0.005-0.08g/ml, add optional medicine and optional roentgenopaque material forms mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with in the immiscible organic solvent of water, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b2: add in the solution containing 0.005-0.15g/ml magnetic metal ion, macromolecular material positively charged for optional 0.002-0.131g/ml and optional 0.002-0.16g/ml nonmagnetic metal ion in the step a2 Emulsion obtained or emulsion, more than 60min is stirred when low whipping speed is 200-2000rpm, preferred 80-120min, separates, washs the microgranule prepared;
Step c2: the microgranule that step b2 prepares is joined in the mixed solution containing cross-linking agent and optional catalyst, after reaction, it is preferable that after reaction 8-24h, separate, wash, obtain embolism materials.
In above-mentioned emulsion process, when embolism materials is without positively charged macromolecular material, also can cross-linking agent (and optional catalyst) be joined in the solution containing magnetic metal ion and optional nonmagnetic metal ion, again this solution is joined in the step a2 Emulsion obtained or emulsion, after reaction, separate, wash, obtain embolic particles.
Further, described preparation method is emulsion process (also referred to as double emulsion), comprises the following steps:
Step a3: sodium alginate is configured to sodium alginate aqueous solution, add optional medicine and optional roentgenopaque material forms mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with in the immiscible organic solvent of water, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b3: prepare the solution containing magnetic metal ion, optionally positively charged macromolecular material and optional nonmagnetic metal ion, then this solution is joined containing surfactant with in the immiscible organic solvent of water, make water-in-oil emulsion;
Step c3: the Emulsion that the Emulsion obtained by step a3 or emulsion obtain with step b3 mixes, stirs more than 60min, it is preferable that 80-120min when low whipping speed is 200-2000rpm, separate, wash the microgranule prepared;
Step d3: the microgranule that step c3 prepares is joined in the mixed solution containing cross-linking agent and optional catalyst, after reaction, it is preferable that after reaction 8-24h, separate, wash, obtain embolism materials,
Preferably, above-mentioned emulsion process (double emulsion) comprises the following steps:
Step a3: sodium alginate is configured to the sodium alginate aqueous solution of 0.005-0.08g/ml, add optional medicine and optional roentgenopaque material forms mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with in the immiscible organic solvent of water, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b3: prepare the solution containing 0.005-0.15g/ml magnetic metal ion, macromolecular material positively charged for optional 0.002-0.131g/ml and optional 0.002-0.16g/ml nonmagnetic metal ion, then this solution is joined containing surfactant with in the immiscible organic solvent of water, make water-in-oil emulsion;
Step c3: the Emulsion that the Emulsion obtained by step a3 or emulsion obtain with step b3 mixes, stirs more than 60min, it is preferable that 80-120min when low whipping speed is 200-2000rpm, separate, wash the microgranule prepared;
Step d3: the microgranule that step c3 prepares is joined in the mixed solution containing cross-linking agent and optional catalyst, after reaction, it is preferable that after reaction 8-24h, separate, wash, obtain embolism materials.
In above-mentioned emulsion process (double emulsion), also the mixed solution containing cross-linking agent and optional catalyst can be directly added in the mixed liquor (mixed liquor that the Emulsion that the Emulsion obtained by step a3 or emulsion obtain with step b3 obtains after mixing) of step c3, after reaction, separate, wash, obtain embolism materials.
The present invention further provides above-mentioned embolism materials in preparation for treating tumor, such as hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma or malignant breast tumor, or vascular malformation or for the purposes in the medicine of hemostasis etc.
Compared with prior art, the present invention adopts the embolism materials that can be detected by MRI prepared by sodium alginate and magnetic metal ion etc. at least to have the advantage that
1, complication is the principal risk of thromboembolism operation, maximum with dystopy thromboembolism and the harm brought of backflowing, adopt the embolism materials of the present invention, enable a physician to be monitored in real time suppository location by MRI, can take steps in time avoid dystopy thromboembolism and backflow, thus improve the efficacy and saferry of embolotherapy; Additionally, accurately judge that thromboembolism terminal is the key of thromboembolism successful surgery, thromboembolism not exclusively can cause continuing or recurrence of symptom, inject too much suppository to be then likely to cause dystopy thromboembolism, cause that normal structure is damaged, and adopt the embolism materials of the present invention to make doctor can pass through MRI after having injected suppository and directly detect suppository endovascular filling situation (whether Ink vessel transfusing has the degree that suppository is filled and filled), judge thromboembolism terminal more exactly, thus improve the efficacy and saferry of embolotherapy.
2, the embolism materials that can be detected by MRI prepared by the present invention can be used for the Therapy study of clinic: can directly detect suppository distributed in three dimensions in vivo by MRI, the relatively relation between thromboembolism result and the curative effect of various dose, different materials, variable concentrations suppository, thus being conducive to doctor to update embolization technique, improve the efficacy and safety of embolotherapy.
3, the embolism materials that can be detected by MRI of the present invention is adopted, make doctor can pass through MRI in Embolization and in real time, directly monitor suppository present position, estimate effect of embolization and to the length being plugged vessel segment, whether thromboembolism is fine and close, the trends of vascular embolization etc. make accurate judgement, it is simple to postoperative check.
4, the embolism materials of the present invention is adopted to make doctor can detect suppository distribution situation in vivo by MRI after thromboembolism, whether uniform in endovascular distribution including suppository, whether the distribution of suppository changes, whether degradable suppository there is degraded etc., thus being conducive to postoperative evaluation blood vessel by the degree of thromboembolism, instruct for treating offer further.
5, the embolism materials that can be detected by MRI of the present invention is used it can be avoided that the rasdiation damage that causes because of X-radiological survey X of patient.
6, after adding medicine in the embolism materials of the present invention, embolotherapy and Drug therapy can be made to play synergism, make doctor that MRI can be utilized directly to monitor and control position and the density of suppository, realize the target administration function of medicine carrying suppository better, make medicine at local sustained release, maintain longer action time, higher local concentration, and reduce the toxic and side effects that medicine causes at other position of whole body.
7, after adding roentgenopaque material in the embolism materials of the present invention, embolism materials also can be detected by x-ray, including DSA and CT(ComputedTomography, computed tomography) detection, be conducive to doctor and patient to select suitable detection method according to armarium and self-condition.
8, the present invention adopts the embolism materials that can be detected by MRI that sodium alginate is prepared with magnetic metal ion etc., and preparation technology is simple, and cost is low, is suitable for large-scale industrial production, is conducive to clinical expansion and the application of product.
Accompanying drawing explanation
Hereinafter, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:
Fig. 1 is the optical microscope photograph of the embolic particles of the embodiment of the present invention 4 preparation;
Fig. 2 is the optical microscope photograph of the comparison microgranule of the embodiment of the present invention 4 preparation;
Fig. 3 is embolic particles prepared by the embodiment of the present invention 4 and the external MRI detection image compareing microgranule;
The embolic particles that Fig. 4 is the embodiment of the present invention 4 preparation detects image at the subcutaneous MRI of mice;
Fig. 5 is the drug release profiles of the load amycin embolic particles of the embodiment of the present invention 9 preparation;
Fig. 6 is the drug release profiles of the load Sorafenib embolic particles of the embodiment of the present invention 10 preparation.
Detailed description of the invention
Referring to specific embodiment, the present invention is described. It will be appreciated by those skilled in the art that these embodiments are merely to illustrate the present invention, its scope not limited the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is conventional method. Medicine material used in following embodiment, reagent, material etc., if no special instructions, be commercially available purchase product.
Embodiment 1The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.005g/ml;
2) under stirring, sodium alginate aqueous solution step 1) prepared instills in the solution of the trivalent gadolinium ion containing 50g (0.045g/ml), after after dripping, continues stirring 120min and reacts fully, obtain embolic particles after separation, washing.
Embodiment 2The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.01g/ml, 5g Bleomycin A5 is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (solution);
2) under stirring, mixed liquor step 1) prepared instills in the solution containing 1000g ferric ion (0.12g/ml), 1000g calcium ion (0.12g/ml) and 100g chitosan (0.012g/ml), after after dripping, continue stirring 120min to react fully, after separation, washing, obtain embolic particles;
3) by step 2) prepare microgranule be soaked in the mixed solution containing 4g formaldehyde and 1g hydrochloric acid, cross-linking reaction 24h, separate, washing after obtain embolic particles.
Embodiment 3The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.05g/ml, 0.01g tantalum powder is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (suspension);
2) under stirring, mixed liquor prepared for step 1) is instilled in the solution containing 23g ferric ion (0.01g/ml) and 60g chitosan (0.026g/ml), after after dripping, continue stirring 120min and react fully, separate, wash the microgranule prepared;
3) by step 2) prepare microgranule be soaked in the mixed solution containing 250g formaldehyde and 150g sulphuric acid, cross-linking reaction 12h, separate, washing after obtain embolic particles.
Embodiment 4The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.03g/ml sodium alginate aqueous solution;
2) under stirring, sodium alginate aqueous solution step 1) prepared instills in the solution of the trivalent holmium ion containing 6g (0.03g/ml) and 7.5g chitosan (0.038g/ml), after after dripping, continue stirring 120min and react fully, separate, wash the microgranule prepared;
3) by step 2) prepare microgranule be soaked in the mixed solution containing 160g formaldehyde and 11g hydrochloric acid, cross-linking reaction 12h, separate, washing after obtain embolic particles, this embolic particles form under an optical microscope is as shown in Figure 1. As can be seen from Figure 1, the embolic particles of preparation is substantially spherical in shape, and between granule, dispersibility is better, soap-free emulsion polymeization and agglomeration.
It addition, adopt method similar to above to be prepared without the comparison microgranule (i.e. blank embolic particles) of magnetic metal ion, comprise the following steps:
1) 1g sodium alginate is configured to 0.03g/ml sodium alginate aqueous solution;
2) under stirring, sodium alginate aqueous solution step 1) prepared instills containing 1.5g divalent calcium ions (0.0075g/ml, identical with the mole of 6g trivalent holmium ion) and the solution of 7.5g chitosan (0.038g/ml) in, after after dripping, continue stirring 120min to react fully, separate, wash the microgranule prepared;
3) by 2) prepare microgranule be soaked in the mixed solution containing 160g formaldehyde and 11g hydrochloric acid, cross-linking reaction 12h, separate, washing obtain calcium alginate microgranule, this calcium alginate microgranule form under an optical microscope is as shown in Figure 2.
Embodiment 5The preparation of embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.07g/ml, 0.01g iodized oil is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (oil-in-water emulsion);
2) mixed liquor in step 1) is joined in the mixed liquor containing 0.1g sorbester p17 and 20g liquid paraffin, stir 20min when low whipping speed is 200rpm, obtain Water-In-Oil oil-in emulsion;
3) to step 2) emulsion that obtains adds the mixed solution of the trivalent holmium ion containing 0.8g (0.15g/ml), 0.01g calcium ion (0.002g/ml) and 0.7g chitosan (0.131g/ml), stir 80min when low whipping speed is 2000rpm, separate, wash the microgranule prepared;
4) microgranule that step 3) prepares is soaked in the mixed solution containing 6g glutaraldehyde and 2g hydrochloric acid, cross-linking reaction 8h, obtain embolic particles after separation, washing.
Embodiment 6The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.08g/ml sodium alginate aqueous solution, 0.05g tantalum powder is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (suspension);
2) under stirring, mixed liquor step 1) prepared instills in the solution of the trivalent ytterbium ion containing 0.1g (0.005g/ml), 0.01g calcium ion (0.0005g/ml) and 0.2g gelatin (0.01g/ml), after after dripping, continue stirring 120min to react fully, separate, wash the microgranule prepared;
3) by step 2) prepare microgranule be soaked in the mixed solution containing 80g glutaraldehyde and 6.6g hydrochloric acid, cross-linking reaction 12h, separate, washing after obtain embolic particles.
Embodiment 7The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.05g/ml, 0.1g Sutent is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (suspension);
2) under stirring, mixed liquor step 1) prepared uses electrostatic drop generator to instill in the solution of the bivalence barium ions containing 2g (0.033g/ml), 4.2g trivalent gadolinium ion (0.07g/ml) and 0.3g chitosan (0.005g/ml), after after dripping, continue stirring 80min to react fully, separate, wash the microgranule prepared;
3) by step 2) prepare microgranule be soaked in the mixed solution containing 260g glutaraldehyde and 17g hydrochloric acid, cross-linking reaction 12h, separate, washing after obtain embolic particles.
Embodiment 8The preparation of embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.08g/ml, 2g iodized oil is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (oil-in-water emulsion);
2) mixed liquor of step 1) is joined in the mixed liquor containing 0.2g sorbester p17 and 40g liquid paraffin, under 500rpm mixing speed, stir 10min, obtain Water-In-Oil oil-in emulsion;
3) to step 2) emulsion that obtains adds the mixed solution containing 2g trivalent dysprosium ion (0.075g/ml), 0.1g calcium ion (0.004g/ml) and 0.2g gelatin (0.008g/ml), under 600rpm mixing speed, continue stirring 100min, separate, wash the microgranule prepared;
4) microgranule that step 3) prepares is soaked in the mixed solution containing 100g formaldehyde and 6.3g hydrochloric acid, cross-linking reaction 24h, obtain embolic particles after separation, washing.
Embodiment 9The preparation of medicine carrying embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.01g/ml, 0.3g amycin is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (solution);
2) mixed liquor of step 1) is joined in the mixed liquor containing 50g sorbester p17 and 400g hexamethylene, under 1700rpm mixing speed, stir 30min, obtain water-in-oil emulsion;
3) to step 2) Emulsion that obtains adds the mixed solution of the trivalent holmium ion containing 12g (0.12g/ml) and 1g chitosan (0.01g/ml), under 200rpm mixing speed, stir 120min, separate, microgranule that washing prepares;
4) microgranule that step 3) prepares is soaked in the solution containing 250g glutaraldehyde, cross-linking reaction 12h, obtain embolic particles after separation, washing;
Embodiment 10The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.03g/ml, 0.05g Sorafenib is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (solution);
2) under stirring, mixed liquor step 1) prepared instills in the solution of the trivalent gadolinium ion containing 3g (0.008g/ml), 0.3g calcium ion (0.0008g/ml) and 6.7g chitosan (0.018g/ml), after after dripping, continue stirring 120min to react fully, separate, wash the microsphere prepared;
3) by step 2) prepare microgranule be soaked in the mixed solution containing 350g formaldehyde and 100g hydrochloric acid, cross-linking reaction 12h, separate, washing after obtain embolic particles.
Embodiment 11The preparation of embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.005g/ml, 5g iofendylate is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (oil-in-water emulsion);
2) mixed liquor of step 1) is joined in the mixed liquor containing 60g sorbester p17 and 1200g liquid paraffin, under 2000rpm mixing speed, stir 40min, obtain Water-In-Oil oil-in emulsion;
3) to step 2) emulsion that obtains adds the mixed solution of the trivalent holmium ion containing 18g (0.05g/ml), 20g calcium ion (0.056g/ml) and 2g chitosan (0.006g/ml), under 400rpm mixing speed, continue stirring 100min, separate, wash the microgranule prepared;
4) microgranule that step 3) prepares is soaked in the mixed solution containing 350g formaldehyde and 150g hydrochloric acid, cross-linking reaction 12h, obtain embolic particles after separation, washing.
Embodiment 12The preparation of embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.007g/ml sodium alginate aqueous solution, 0.5g tantalum powder and 0.05g cisplatin is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (suspension);
2) mixed liquor of step 1) is joined in the mixed liquor containing 25g sorbester p17 and 800g liquid paraffin, under 1300rpm mixing speed, stir 15min, obtain water-in-oil emulsion;
3) to step 2) Emulsion that obtains add in the mixed solution of the trivalent holmium ion containing 20g (0.12g/ml), 3g calcium ion (0.018g/ml) and 0.5g gelatin (0.003g/ml); under 1500rpm mixing speed, continue stirring 100min, separate, wash the microgranule prepared;
4) microgranule that step 3) prepares is soaked in the mixed solution containing 4g glutaraldehyde and 1g hydrochloric acid, cross-linking reaction 15h, obtain embolic particles after separation, washing.
Embodiment 13The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.009g/ml sodium alginate aqueous solution, then 1g paclitaxel is suspended in 2g iodized oil, oil phase is joined in sodium alginate aqueous solution, stir, obtain mixed liquor (oil-in-water emulsion);
2) under stirring, mixed liquor prepared for step 1) is instilled in the solution of the trivalent gadolinium ion containing 5g (0.006g/ml), after after dripping, continue stirring 120min and react fully, separate, wash the microgranule prepared;
3) by step 2) prepare microgranule be soaked in the mixed solution containing 6g glutaraldehyde and 2g hydrochloric acid, cross-linking reaction 20h, separate, washing after obtain embolic particles.
Embodiment 14The preparation of embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.02g/ml sodium alginate aqueous solution, 0.05g tantalum powder and 5g cisplatin is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (suspension);
2) mixed liquor of step 1) is joined in the mixed liquor containing 10g sorbester p17 and 200g liquid paraffin, under 1000rpm mixing speed, stir 35min, obtain water-in-oil emulsion;
3) to step 2) Emulsion that obtains adds in the solution of the trivalent holmium ion containing 6g (0.09g/ml), under 1000rpm mixing speed, continue stirring 100min, separate, microgranule that washing prepares;
4) microgranule that step 3) prepares is soaked in the solution containing 120g glutaraldehyde, cross-linking reaction 15h, obtain embolic particles after separation, washing.
Embodiment 15The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.007g/ml sodium alginate aqueous solution, then 0.2g paclitaxel is suspended in 5g iodized oil, oil phase is joined in sodium alginate aqueous solution, stir, obtain mixed liquor (oil-in-water emulsion);
2) under stirring, mixed liquor prepared for step 1) is instilled in the solution of the trivalent gadolinium ion containing 210g (0.05g/ml), after after dripping, continue stirring 90min and react fully, separate, wash the microgranule prepared;
3) by step 2) prepare microgranule be soaked in the solution containing 100g formaldehyde, cross-linking reaction 8h, separate, washing after obtain embolic particles.
Embodiment 16The preparation of embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.009g/ml sodium alginate aqueous solution, 0.1g Sorafenib is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (suspension);
2) mixed liquor of step 1) is joined in the mixed liquor containing 8g sorbester p17 and 250g isobutyltrimethylmethane., under 1500rpm mixing speed, stir 25min, obtain water-in-oil emulsion;
3) solution of preparation trivalent holmium ion containing 8g (0.09g/ml), adds it in the mixed liquor containing 7g sorbester p17 and 200g liquid paraffin, stirring, obtains water-in-oil emulsion;
4) by step 2) and step 3) obtain Emulsion mixing, when low whipping speed is 1700rpm continue stirring 100min, separate, washing prepare microgranule.
Embodiment 17The preparation of embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.05g/ml sodium alginate aqueous solution, 1g lignocaine is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (solution);
2) mixed liquor of step 1) is joined in the mixed liquor containing 2g sorbester p17 and 80g liquid paraffin, under 400rpm mixing speed, stir 30min, obtain water-in-oil emulsion;
3) to step 2) Emulsion that obtains adds in the solution of the trivalent holmium ion containing 0.1g (0.005g/ml), under 900rpm mixing speed, continue stirring 100min, separate, microgranule that washing prepares;
4) microgranule that step 3) prepares is soaked in the solution containing 60g glutaraldehyde, cross-linking reaction 15h, obtain embolic particles after separation, washing.
Embodiment 18The preparation of embolic particles
The present embodiment adopts dropping preparation method to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to 0.06g/ml sodium alginate aqueous solution, 0.6g Sorafenib and 1g tantalum powder is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (suspension);
2) under stirring, mixed liquor step 1) prepared instills in the solution of the trivalent gadolinium ion containing 20g (0.12g/ml), 20g calcium ion (0.12g/ml) and 20g chitosan (0.12g/ml), after after dripping, continue stirring 100min and react fully, separate, wash the microsphere prepared;
3) by step 2) prepare microgranule be soaked in the mixed solution containing 40g formaldehyde and 45g hydrochloric acid, cross-linking reaction 15h, separate, washing after obtain embolic particles.
Embodiment 19The preparation of embolic particles
The present embodiment adopts emulsion process to prepare embolic particles, comprises the following steps:
1) 1g sodium alginate is configured to the sodium alginate aqueous solution of 0.03g/ml, 0.6g Sorafenib and 1g iofendylate is joined in sodium alginate aqueous solution, stirs, obtain mixed liquor (oil-in-water emulsion);
2) mixed liquor of step 1) is joined in the mixed liquor containing 10g sorbester p17 and 40g liquid paraffin, under 600rpm mixing speed, stir 20min, obtain Water-In-Oil oil-in Emulsion;
3) solution of preparation trivalent holmium ion containing 1g (0.016g/ml), 10g calcium ion (0.16g/ml) and 0.1g gelatin (0.002g/ml), joins in the mixed liquor containing 25g sorbester p17 and 60g liquid paraffin by solution, stirring, obtains water-in-oil emulsion;
4) by step 2) and step 3) obtain Emulsion mixing, when low whipping speed is 1200rpm continue stirring 90min, separate, washing prepare microgranule;
5) microgranule that step 4) prepares is added in the mixed solution containing 180g formaldehyde and 40g hydrochloric acid, after reaction 20h, separates, wash, obtain embolism materials.
The external MRI detection of embolic particles
Embolic particles (containing magnetic metal ion) and comparison microgranule (without magnetic metal ion) to embodiment 4 preparation carry out MRI vitro detection. Culture dish adds agar solution 1 centimetre high, is after agaropectin until its cooled and solidified, embolic particles (containing magnetic metal ion) and comparison microgranule (without magnetic metal ion) are placed individually on agaropectin, repave one layer of agaropectin 1 centimetre high. Sample in agaropectin carries out magnetic resonance detection, and nuclear magnetic resonance result is as shown in Figure 3. Fig. 3 shows the embolic particles (upper strata containing magnetic metal ion, black) with compare microgranule (lower floor without magnetic metal ion, white) external MRI detect image (from left to right the number of two-layer microgranule respectively 1,2,3,4,5), as can be seen from Figure 3, the present invention adopts embolic particles prepared by sodium alginate and magnetic metal ion directly can be clearly detected by MRI, and the comparison microgranule without magnetic metal ion then can not be detected by MRI.
Embolic particles is in the subcutaneous MRI detection of mice
From the embolic particles of embodiment 4 preparation, screen out the microgranule of 100-300 ��m, in microgranule suspendible to the carboxymethylcellulose sodium solution of 1%, mice will be injected subcutaneous. Being placed under 3TMRI to be scanned mice, testing result is as shown in Figure 4. Fig. 4 illustrates that embolic particles detects image at the subcutaneous MRI of mice, and the external white bright spot of Fig. 4 small mouse is vitamin E capsule, and white arrow indicates injection site, and result shows, can be detected by MRI at the subcutaneous embolic particles of mice.
The release experiment of medicine carrying embolic particles
T-shaped tube method is adopted to measure the release in vitro carrying amycin embolic particles of embodiment 9 preparation. Experimentation is as follows: adding the phosphate buffer of 200mlpH7.4 in T-shaped pipe as release medium, buffer mobility is 50ml/min, and bath temperature is 37 DEG C. 1ml is carried amycin embolic particles and is placed in the bottom of T-shaped pipe, in 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, take out 5ml release medium respectively and supply isothermal, isopyknic fresh dissolution medium immediately, under 233nm wavelength, measuring absorbance, calculate release amount according to standard curve. The drug release profiles of load amycin embolic particles is as shown in Figure 5. As seen from Figure 5, load amycin embolic particles is very fast in front 6h rate of release, cumulative release about 75% during 6h, cumulative release about 89% during 24h.
T-shaped tube method is adopted to measure the release in vitro carrying Sorafenib embolic particles of embodiment 10 preparation. Experimentation is as follows: adding the phosphate buffer of 200mlpH7.4 in T-shaped pipe as release medium, buffer mobility is 50ml/min, and bath temperature is 37 DEG C. 1ml is carried Sorafenib embolic particles and is placed in the bottom of T-shaped pipe, in 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, take out 5ml release medium respectively and supply isothermal, isopyknic fresh dissolution medium immediately, under 265nm wavelength, measuring absorbance, calculate release amount according to standard curve.The drug release profiles of load Sorafenib embolic particles is as shown in Figure 6. As seen from Figure 6, load Sorafenib embolic particles is very fast in front 4h rate of release, cumulative release about 60% during 4h, cumulative release about 80% during 24h.
Specific description of embodiments of the present invention above is not limiting as the present invention, and those skilled in the art can be variously modified according to the present invention or deform, and without departing from the spirit of the present invention, all should belong to scope of the following claims of the present invention.
Claims (36)
1. an embolism materials, it is made up of reactant feed, described reactant feed includes: the magnetic metal ion more than sodium alginate of 1 weight portion and 0.1 weight portion, wherein, sodium alginate forms coordination compound with magnetic metal ion, and, described reactant feed farther includes the positively charged macromolecular material of 0.1-100 weight portion and 4-500 weight portion auxiliary agent, described auxiliary agent is cross-linking agent or the mixture being made up of cross-linking agent and catalyst, and include alternatively: the roentgenopaque material of 0.01-5 weight portion, more than 0.01 weight portion nonmagnetic metal ion or 0.05-5 weight portion medicine, and described embolism materials is particle diameter is the microgranule of 1-2000 ��m, described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, one or more in thulium or ytterbium ion, described nonmagnetic metal ion is selected from calcium, aluminum, barium, plumbous, cadmium, copper, one or more in strontium or zinc ion, described positively charged macromolecular material is biocompatible polymer material, described catalyst is selected from hydrochloric acid, sulphuric acid, one or more in phosphoric acid or acetic acid, described cross-linking agent is selected from formaldehyde, acetaldehyde, Biformyl, butyraldehyde, boric acid, Borax, glutaraldehyde, one or more in hexandial or genipin, described roentgenopaque material is selected from iodized oil, iofendylate, one or more in tantalum powder or barium sulfate, described medicine is selected from antitumor drug, local anaesthesia medicine, one or more in antipyretic-antalgic anti-inflammatory agent thing or antibiotic medicine.
2. embolism materials according to claim 1, it is characterised in that described microgranule is microsphere.
3. embolism materials according to claim 1, it is characterised in that described embolism materials adopts emulsion process to prepare, and described reactant feed includes:
4. embolism materials according to claim 3, it is characterised in that described reactant feed includes:
5. embolism materials according to claim 1, it is characterised in that described embolism materials adopts dropping preparation method to prepare, and described reactant feed includes:
6. embolism materials according to claim 5, it is characterised in that described reactant feed includes:
7. the embolism materials according to claim 3 or 4, it is characterised in that one or both in spans surfactant or the mixture that is made up of spans surfactant and Tweens surfactant of described surfactant;
Described organic solvent is organic solvent immiscible with water.
8. embolism materials according to claim 1, it is characterised in that described positively charged macromolecular material is one or both in chitosan or gelatin.
9. embolism materials according to claim 1, it is characterized in that, described antitumor drug is selected from one or more in amycin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel, Docetaxel, 5-fluorouracil, Bleomycin A5, Sutent, Sorafenib, gefitinib, imatinib, PTK787 or its salt.
10. embolism materials according to claim 1, it is characterized in that, described local anaesthesia medicine selected from procaine, chloroprocaine, hydroxyprocaine, tetracaine, parethoxycaine, on foot hold in the palm in caine, dimethocaine, lignocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, supernatural power caine, quinisocaine, phenacaine or its salt one or more.
11. embolism materials according to claim 1, it is characterized in that, described antipyretic-antalgic anti-inflammatory agent thing is selected from one or more in aspirin, magnesium salicylate, sodium salicylate, choline magnesium trisalicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, fenoprofen, naproxen, nabumetone, piroxicam, Phenylbutazone, acetaminophen, diclofenac, venlofen, ketone ibuprofen, ketorolac, four clofenamic acides, sulindac or tolmetin.
12. embolism materials according to claim 1, it is characterized in that, described antibiotic medicine is selected from penicillin, oxacillin sodium, ampicillin, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid, sulbactam, oxytetracycline, tetracycline, demeclocycline, streptomycin, kanamycin A, gentamycin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribostamycin, bekanamycin, framycetin, paromomycin, erythromycin, Roxithromycin, clarithromycin, azithromycin, chloromycetin, ciclosporin, one or more in lincomycin or its salt.
13. embolism materials according to claim 7, it is characterised in that described organic solvent is selected from one or more in mineral oil, vegetable oil, silicone oil, alkene, alcohol, aldehyde, amine, ether or ketone.
14. embolism materials according to claim 7, it is characterised in that described organic solvent is liquid paraffin, isobutyltrimethylmethane. or hexamethylene.
15. the preparation method according to claim 1 to 2, embolism materials according to any one of 5 to 6 and 8 to 12, described preparation method is dropping preparation method, comprises the following steps:
Step a1: sodium alginate is configured to sodium alginate aqueous solution, adds optional medicine and optional roentgenopaque material forms mixed liquor;
Step b1: under stirring, sodium alginate soln in step a1 or mixed liquor are instilled in the solution containing magnetic metal ion, positively charged macromolecular material and optional nonmagnetic metal ion, after after dripping, stir more than 60min, separate, wash the microgranule prepared;
Step c1: the microgranule obtained by step b1 joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, separates, washs, obtain embolism materials.
16. preparation method according to claim 15, it is characterised in that in described step b1, stir 80-120min.
17. preparation method according to claim 15, it is characterized in that, in described step b1, electrostatic drop generator is used the sodium alginate soln in step a1 or mixed liquor to be instilled in the solution containing magnetic metal ion, positively charged macromolecular material and optional nonmagnetic metal ion.
18. preparation method according to claim 15, it is characterised in that in described step c1, after reaction 8-24h, separate, wash, obtain embolism materials.
19. the preparation method according to any one of claim 15 to 18, it is characterised in that described preparation method comprises the following steps:
Step a1: sodium alginate is configured to the sodium alginate aqueous solution of 0.005-0.08g/ml, adds optional medicine and optional roentgenopaque material forms mixed liquor;
Step b1: under stirring, sodium alginate soln in step a1 or mixed liquor are instilled in the solution containing 0.005-0.12g/ml magnetic metal ion, macromolecular material positively charged for 0.005-0.12g/ml and optional 0.0005-0.12g/ml nonmagnetic metal ion, after after dripping, stirring more than 60min, separates, washs the microgranule prepared;
Step c1: the microgranule obtained by step b1 joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, separates, washs, obtain embolism materials.
20. preparation method according to claim 19, it is characterised in that in described step b1, stir 80-120min.
21. preparation method according to claim 19, it is characterized in that, in described step b1, electrostatic drop generator is used the sodium alginate soln in step a1 or mixed liquor to be instilled in the solution containing magnetic metal ion, positively charged macromolecular material and optional nonmagnetic metal ion.
22. preparation method according to claim 19, it is characterised in that in described step c1, after reaction 8-24h, separate, wash, obtain embolism materials.
23. the preparation method of the embolism materials according to any one of Claims 1-4 and 7 to 14, described preparation method is emulsion process, comprises the following steps:
Step a2: sodium alginate is configured to sodium alginate aqueous solution, add optional medicine and optional roentgenopaque material forms mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant and with in the mixed liquor of the immiscible organic solvent of water, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b2: add in the solution containing magnetic metal ion, positively charged macromolecular material and optional nonmagnetic metal ion in the step a2 Emulsion obtained or emulsion, stir more than 60min when low whipping speed is 200-2000rpm, separate, wash the microgranule prepared;
Step c2: join in the mixed solution containing cross-linking agent and optional catalyst by the microgranule that step b2 prepares, after reaction, separates, washs, obtain embolism materials.
24. preparation method according to claim 23, it is characterised in that in described step b2, stir 80-120min.
25. preparation method according to claim 23, it is characterised in that in described step c2, after reaction 8-24h, separate, wash, obtain embolism materials.
26. the preparation method according to any one of claim 23 to 25, it is characterised in that described preparation method comprises the following steps:
Step a2: sodium alginate is configured to the sodium alginate aqueous solution of 0.005-0.08g/ml, add optional medicine and optional roentgenopaque material forms mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with in the immiscible organic solvent of water, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b2: add in the solution containing 0.005-0.15g/ml magnetic metal ion, macromolecular material positively charged for 0.002-0.131g/ml and optional 0.002-0.16g/ml nonmagnetic metal ion in the step a2 Emulsion obtained or emulsion, stir more than 60min when low whipping speed is 200-2000rpm, separate, wash the microgranule prepared;
Step c2: join in the mixed solution containing cross-linking agent and optional catalyst by the microgranule that step b2 prepares, after reaction, separates, washs, obtain embolism materials.
27. preparation method according to claim 26, it is characterised in that in described step b2, stir 80-120min.
28. preparation method according to claim 26, it is characterised in that in described step c2, after reaction 8-24h, separate, wash, obtain embolism materials.
29. the preparation method of the embolism materials according to any one of Claims 1-4 and 7 to 14, described preparation method is emulsion process, comprises the following steps:
Step a3: sodium alginate is configured to sodium alginate aqueous solution, add optional medicine and optional roentgenopaque material forms mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with in the immiscible organic solvent of water, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b3: prepare the solution containing magnetic metal ion, positively charged macromolecular material and optional nonmagnetic metal ion, then this solution is joined containing surfactant with in the immiscible organic solvent of water, make water-in-oil emulsion;
Step c3: the Emulsion that the Emulsion obtained by step a3 or emulsion obtain with step b3 mixes, stirs more than 60min when low whipping speed is 200-2000rpm, separate, wash the microgranule prepared;
Step d3: join in the mixed solution containing cross-linking agent and optional catalyst by the microgranule that step c3 prepares, after reaction, separates, washs, obtain embolism materials.
30. preparation method according to claim 29, it is characterised in that in described step c3, stir 80-120min.
31. preparation method according to claim 29, it is characterised in that in described step d3, after reaction 8-24h, separate, wash, obtain embolism materials.
32. the preparation method according to any one of claim 29 to 31, it is characterised in that described preparation method is emulsion process, comprises the following steps:
Step a3: sodium alginate is configured to the sodium alginate aqueous solution of 0.005-0.08g/ml, add optional medicine and optional roentgenopaque material forms mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with in the immiscible organic solvent of water, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b3: prepare the solution containing 0.005-0.15g/ml magnetic metal ion, macromolecular material positively charged for 0.002-0.131g/ml and optional 0.002-0.16g/ml nonmagnetic metal ion, then this solution is joined containing surfactant with in the immiscible organic solvent of water, make water-in-oil emulsion;
Step c3: the Emulsion that the Emulsion obtained by step a3 or emulsion obtain with step b3 mixes, stirs more than 60min when low whipping speed is 200-2000rpm, separate, wash the microgranule prepared;
Step d3: join in the mixed solution containing cross-linking agent and optional catalyst by the microgranule that step c3 prepares, after reaction, separates, washs, obtain embolism materials.
33. preparation method according to claim 32, it is characterised in that in described step c3, stir 80-120min.
34. preparation method according to claim 32, it is characterised in that in described step d3, after reaction 8-24h, separate, wash, obtain embolism materials.
35. the embolism materials according to any one of claim 1 to 14 in preparation for treating tumor or vascular malformation or for the purposes in the medicine that stops blooding.
36. purposes according to claim 35, it is characterised in that described tumor is hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma or malignant breast tumor.
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| TWI681781B (en) * | 2016-11-17 | 2020-01-11 | 大員生醫股份有限公司 | Hydrophilic microsphere made from pharmaceutical excipients for embolization therapy |
| CN106620829A (en) * | 2017-03-13 | 2017-05-10 | 安疗生命科学（武汉）有限公司 | Developing embolism material and preparation method thereof |
| CN116115818A (en) * | 2021-11-12 | 2023-05-16 | 刘庄 | Active metal microsphere, composite embolic agent based on active metal microsphere and application of composite embolic agent |
| CN114870064A (en) * | 2022-05-09 | 2022-08-09 | 上海玮沐医疗科技有限公司 | Photo-curing composite hydrogel containing contrast agent and preparation and use methods thereof |
| CN117085166A (en) * | 2023-08-24 | 2023-11-21 | 首都医科大学附属北京同仁医院 | Tantalum-calcium alginate thrombin microsphere and preparation method and application thereof |
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Effective date of registration: 20211227 Address after: 100083 Room 606, 6th floor, building 9, 35 Huayuan North Road, Haidian District, Beijing Patentee after: HYGEA MEDICAL TECHNOLOGY Co.,Ltd. Address before: 100191 Department of pharmacy, Department of medicine, Peking University, 38 Xueyuan Road, Haidian District, Beijing Patentee before: Peking University |