CN103536970A - Embolic material, and preparation method and use thereof - Google Patents
Embolic material, and preparation method and use thereof Download PDFInfo
- Publication number
- CN103536970A CN103536970A CN201310513272.7A CN201310513272A CN103536970A CN 103536970 A CN103536970 A CN 103536970A CN 201310513272 A CN201310513272 A CN 201310513272A CN 103536970 A CN103536970 A CN 103536970A
- Authority
- CN
- China
- Prior art keywords
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- sodium alginate
- microgranule
- metal ion
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000000463 material Substances 0.000 title claims abstract description 128
- 238000002360 preparation method Methods 0.000 title claims abstract description 85
- 230000003073 embolic effect Effects 0.000 title abstract description 5
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 77
- 239000000376 reactant Substances 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 208000005189 Embolism Diseases 0.000 claims description 169
- 239000004531 microgranule Substances 0.000 claims description 160
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 121
- 235000010413 sodium alginate Nutrition 0.000 claims description 121
- 239000000661 sodium alginate Substances 0.000 claims description 121
- 229940005550 sodium alginate Drugs 0.000 claims description 121
- 208000001435 Thromboembolism Diseases 0.000 claims description 104
- 238000003756 stirring Methods 0.000 claims description 84
- 238000005406 washing Methods 0.000 claims description 66
- 239000007864 aqueous solution Substances 0.000 claims description 55
- 239000000243 solution Substances 0.000 claims description 51
- 239000000839 emulsion Substances 0.000 claims description 50
- 239000003814 drug Substances 0.000 claims description 43
- 239000011259 mixed solution Substances 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 239000003431 cross linking reagent Substances 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 27
- 238000002156 mixing Methods 0.000 claims description 23
- 238000004945 emulsification Methods 0.000 claims description 21
- 239000003921 oil Substances 0.000 claims description 20
- 239000004094 surface-active agent Substances 0.000 claims description 20
- 239000007762 w/o emulsion Substances 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 18
- -1 ytterbium ion Chemical class 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 12
- 229920001661 Chitosan Polymers 0.000 claims description 12
- 229910052689 Holmium Inorganic materials 0.000 claims description 12
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 12
- 229960003787 sorafenib Drugs 0.000 claims description 12
- 229940057995 liquid paraffin Drugs 0.000 claims description 11
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 claims description 8
- 229930195573 Amycin Natural products 0.000 claims description 8
- 235000019198 oils Nutrition 0.000 claims description 8
- 229920000159 gelatin Polymers 0.000 claims description 7
- 235000019322 gelatine Nutrition 0.000 claims description 7
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 108010010803 Gelatin Proteins 0.000 claims description 6
- 239000012752 auxiliary agent Substances 0.000 claims description 6
- 239000008273 gelatin Substances 0.000 claims description 6
- 235000011852 gelatine desserts Nutrition 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 230000003115 biocidal effect Effects 0.000 claims description 5
- 239000004005 microsphere Substances 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- 230000003068 static effect Effects 0.000 claims description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 4
- 206010002091 Anaesthesia Diseases 0.000 claims description 4
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 4
- IWRUDYQZPTVTPA-UHFFFAOYSA-N Iophendylate Chemical compound CCOC(=O)CCCCCCCCC(C)C1=CC=CC=C1I IWRUDYQZPTVTPA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 4
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
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- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 4
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 4
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- 150000002576 ketones Chemical class 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 claims description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 3
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010027457 Metastases to liver Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
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- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052769 Ytterbium Inorganic materials 0.000 claims description 3
- 229920000249 biocompatible polymer Polymers 0.000 claims description 3
- 108700004675 bleomycetin Proteins 0.000 claims description 3
- QYOAUOAXCQAEMW-UTXKDXHTSA-N bleomycin A5 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCNCCCCN)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QYOAUOAXCQAEMW-UTXKDXHTSA-N 0.000 claims description 3
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960002584 gefitinib Drugs 0.000 claims description 3
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 3
- 229960002411 imatinib Drugs 0.000 claims description 3
- 150000002500 ions Chemical group 0.000 claims description 3
- 229960004194 lidocaine Drugs 0.000 claims description 3
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 claims description 3
- 239000002861 polymer material Substances 0.000 claims description 3
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- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 claims description 3
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- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims description 2
- GHSCYMOJHVOGDJ-UHFFFAOYSA-N 2-(diethylamino)ethyl 4-amino-2-hydroxybenzoate Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1O GHSCYMOJHVOGDJ-UHFFFAOYSA-N 0.000 claims description 2
- XNMYNYSCEJBRPZ-UHFFFAOYSA-N 2-[(3-butyl-1-isoquinolinyl)oxy]-N,N-dimethylethanamine Chemical compound C1=CC=C2C(OCCN(C)C)=NC(CCCC)=CC2=C1 XNMYNYSCEJBRPZ-UHFFFAOYSA-N 0.000 claims description 2
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- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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Images
Abstract
The invention provides an embolic material, and a preparation method and use thereof. The embolic material is prepared from reactant materials; the reactant materials comprise 1 part by weight of sodium alga acid and more than 0.1 part by weight of magnetic metal ions, wherein a coordination compound is formed by the sodium alga acid and the magnetic metal ions. By adopting the embolic material disclosed by the invention, a doctor can directly monitor the position of an embolizing agent by magnetic resonance imaging (MRI) in and after embolization; the curative effect and the safety of embolotherapy are improved.
Description
Technical field
The invention belongs to interventional medicine field, relate to a kind of embolism materials and its production and use.
Background technology
Interventional therapy is 21st century development one of subject the most rapidly.With medical treatment and surgical intervention, run neck and neck at present, become the third therapy system.
Embolotherapy is the important component part of interventional therapy, belongs to invasive treatment.Embolotherapy is under the guiding of medical imaging device, and suppository is introduced to human body by the accurate apparatus such as special seal wire, conduit, artificially occluding vascular and the topical therapeutic that carries out.Thromboembolism therapy all has good curative effect at aspects such as treatment malignant tumor, hysteromyoma, hemangioma, vascular malformation and hemostasis, has become the alternative medicine of part operative treatment.
At present conventional embolism materials mainly contains gelatine microsphere/embolism agent of granule, polyvinyl alcohol microballoon/particle embolic agent and Alginate microparticles suppository etc. clinically.These embolism materials all can not be arrived by existing Clinical detection means direct-detection, and therefore, doctor is difficult to utilize image documentation equipment in Embolization and the postoperative residing position of embolism materials of directly monitoring.In practical application, doctor is by digital subtraction angiography (Digital Subtraction Angiography, DSA), according to the flowing in blood vessel containing diodone, indirectly judges the terminal of the residing position of suppository and thromboembolism.There is certain error in this indirect determination methods.A nearest clinical research shows, by DSA, judge that uterine artery has been had 20% not by complete thromboembolism in the case of complete thromboembolism, postoperative nuclear magnetic resonance (Magnetic Resonance Imaging, MRI) inspection shows that these patients' part uterine artery still has blood to supply.Therefore, how to make embolism materials and can directly by existing Clinical detection means, be detected in Embolization and during postoperative check, to improve the efficacy and saferry of embolotherapy, become this area problem urgently to be resolved hurrily.
Summary of the invention
For the problems referred to above, one object of the present invention is to provide a kind of embolism materials, and this embolism materials makes doctor can directly monitor suppository present position by MRI with postoperative in Embolization, is conducive to improve the efficacy and saferry of embolotherapy.
Another object of the present invention is to provide a kind of preparation method of embolism materials.
Another object of the present invention be to provide a kind of embolism materials for the preparation for the treatment of tumor, for example hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma, malignant breast tumor, or vascular malformation or for the purposes of the medicine that stops blooding etc.
For achieving the above object, the invention provides a kind of embolism materials, it is made by reactant feed, and described reactant feed comprises: the sodium alginate of 1 weight portion and magnetic metal ion more than 0.1 weight portion, wherein, sodium alginate and magnetic metal ion form coordination compound.
Further, described reactant feed further comprises 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 that is comprised of cross-linking agent and catalyst;
Preferably, described reactant feed further comprises one or more in following material: 0.1-100 weight portion macromolecular material, the roentgenopaque material of 0.01-5 weight portion, nonmagnetic metal ion more than 0.01 weight portion, 4-500 weight portion auxiliary agent or 0.05-5 weight portion medicine.
Further, described embolism materials adopts emulsion process preparation, and described reactant feed comprises:
Preferably, described reactant feed comprises:
Further, described embolism materials adopts dropping preparation method preparation, and described reactant feed comprises:
More than sodium alginate 1 weight portion 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 of catalyst 1-150 weight portion weight portion
More than cross-linking agent 4-350 weight portion nonmagnetic metal ion 0.01 weight portion
Preferably, described reactant feed comprises:
Sodium alginate 1 weight portion 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 of catalyst 2-100 weight portion weight portion
Cross-linking agent 6-250 weight portion nonmagnetic metal ion 0.3-1000 weight portion.
Further, described embolism materials is that particle diameter is the microgranule of 1-2000 μ m, and preferable particle size is the microsphere of 1-2000 μ 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, preferably one or both in chitosan or 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 is selected from one or more in procaine, chloroprocaine, hydroxyprocaine, tetracaine, parethoxycaine, empty Tuo Kayin, dimethocaine, lignocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, supernatural power caine, quinisocaine, phenacaine or its salt etc.;
Preferably, described antipyretic-antalgic anti-inflammatory agent thing is selected from one or more in aspirin, magnesium salicylate, sodium salicylate, choline magnesium trisalicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, fenoprofen, naproxen, nabumetone, piroxicam, Phenylbutazone, acetaminophen, diclofenac, venlofen, ketone ibuprofen, ketorolac, four clofenamic acides, sulindac or tolmetin etc.;
Preferably, described antibiotic medicine is selected from beta-lactam antibiotic (penicillin for example, oxacillin sodium, ampicillin, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid or sulbactam), tetracycline antibiotics (oxytetracycline for example, tetracycline or demeclocycline), aminoglycoside antibiotics (streptomycin, kanamycin A, gentamycin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribostamycin, bekanamycin, framycetin or paromomycin), macrolide antibiotics (erythromycin for example, Roxithromycin, clarithromycin or azithromycin) or other antibiotic (chloromycetin for example, ciclosporin or lincomycin) or its salt etc. in one or more,
Preferably, described surfactant be selected from spans surfactant or the mixture that formed by spans surfactant and Tweens surfactant in one or both;
Preferably, described organic solvent is and the immiscible organic solvent of 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., preferred liquid paraffin, isobutyltrimethylmethane. or cyclohexane extraction.
The present invention adopts emulsion process, double emulsion or dropping preparation method etc. by making sodium alginate and magnetic metal ion form coordination compound, makes the embolism materials that can be detected by MRI.In embolism materials of the present invention, can add positively charged biocompatible polymer material, with the coordination compound of wrap negative charge, thereby stop or reduce the release of metal ion and regulate the physicochemical property of embolism materials; Also can in embolism materials of the present invention, add nonmagnetic metal ion, to form coordination compound with sodium alginate, thereby regulate the physicochemical property of embolism materials; Also medicine and/or roentgenopaque material etc. can be dispersed in embolism materials, to strengthen treatment and/or the detected character of embolism materials; Can also add in addition catalyst and cross-linking agent to make sodium alginate, positively charged macromolecular material and cross-linking agent generation cross-linking reaction, to stop or to reduce the release of metal ion and regulate the physicochemical property of embolism materials.
The present invention further provides the preparation method of above-mentioned embolism materials, described preparation method comprises the following steps:
Step a: sodium alginate is mixed with to sodium alginate aqueous solution;
Step b: by the sodium alginate soln in step a and the solution reaction that contains magnetic metal ion, obtain thromboembolism microgranule,
Preferably, described preparation method further comprises:
Step c: the thromboembolism microgranule that step b is obtained joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, separated, washing, obtains embolism materials.
Further, described preparation method is dropping preparation method, comprises the following steps:
Step a1: sodium alginate is mixed with to sodium alginate aqueous solution, adds optional medicine and optional roentgenopaque material to form mixed liquor;
Step b1: under stirring, sodium alginate soln in step a1 or mixed liquor are splashed in the solution containing magnetic metal ion, optional positively charged macromolecular material and optional nonmagnetic metal ion, after dripping, more than stirring 60min, preferred 80-120min, the microgranule separated, washing makes; Preferably, use static drop generator that the sodium alginate soln in step a1 or mixed liquor are splashed in the solution containing magnetic metal ion, optional positively charged macromolecular material and optional nonmagnetic metal ion;
Step c1: the microgranule that step b1 is obtained joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h hour, separated, washing, obtains embolism materials,
Preferably, above-mentioned dropping preparation method comprises the following steps:
Step a1: sodium alginate is mixed with to the sodium alginate aqueous solution of 0.005-0.08g/ml, adds optional medicine and optional roentgenopaque material to form mixed liquor;
Step b1: under stirring, sodium alginate soln in step a1 or mixed liquor are splashed in the solution containing the positively charged macromolecular material of 0.005-0.12g/ml magnetic metal ion, optional 0.005-0.12g/ml and optional 0.0005-0.12g/ml nonmagnetic metal ion, after dripping, more than stirring 60min, preferred 80-120min, the microgranule separated, washing makes; Preferably, use static drop generator that the sodium alginate soln in step a1 or mixed liquor are splashed in the solution containing the positively charged macromolecular material of 0.005-0.12g/ml magnetic metal ion, optional 0.005-0.12g/ml and optional 0.0005-0.12g/ml nonmagnetic metal ion;
Step c1: the microgranule that step b1 is obtained is added in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h hour, separated, washing, obtains embolism materials.
In above-mentioned dropping preparation method, when embolism materials does not contain positively charged macromolecular material, also cross-linking agent (and optional catalyst) can 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 splashed in the mixed solution containing cross-linking agent (and optional catalyst), magnetic metal ion and optional nonmagnetic metal ion, after dripping, stir, separated, washing obtains thromboembolism microgranule.
Further, described preparation method is emulsion process, comprises the following steps:
Step a2: sodium alginate is mixed with to sodium alginate aqueous solution, add optional medicine and optional roentgenopaque material to form mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant and with the mixed liquor of the immiscible organic solvent of water in, 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 Emulsion obtaining to step a2 or emulsion in the solution containing magnetic metal ion, optional positively charged macromolecular material and optional nonmagnetic metal ion, low whipping speed be under 200-2000rpm condition, stir 60min more than, preferred 80-120min, the microgranule separated, washing makes;
Step c2: the microgranule that step b2 is made joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h, separated, washing, obtains embolism materials;
Preferably, above-mentioned emulsion process comprises the following steps:
Step a2: the sodium alginate aqueous solution that sodium alginate is mixed with to 0.005-0.08g/ml, add optional medicine and optional roentgenopaque material to form mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with the immiscible organic solvent of water in, 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 Emulsion obtaining to step a2 or emulsion in the solution containing the positively charged macromolecular material of 0.005-0.15g/ml magnetic metal ion, optional 0.002-0.131g/ml and optional 0.002-0.16g/ml nonmagnetic metal ion, low whipping speed be under 200-2000rpm condition, stir 60min more than, preferred 80-120min, the microgranule separated, washing makes;
Step c2: the microgranule that step b2 is made joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h, separated, washing, obtains embolism materials.
In above-mentioned emulsion process, when embolism materials does not contain positively charged macromolecular material, also cross-linking agent (and optional catalyst) can be joined in the solution containing magnetic metal ion and optional nonmagnetic metal ion, again this solution is joined in the Emulsion or emulsion that step a2 obtains, after reaction, separated, washing, obtain thromboembolism microgranule.
Further, described preparation method is emulsion process (also claiming double emulsion), comprises the following steps:
Step a3: sodium alginate is mixed with to sodium alginate aqueous solution, add optional medicine and optional roentgenopaque material to form mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with the immiscible organic solvent of water in, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b3: preparation is containing the solution of magnetic metal ion, optional positively charged macromolecular material and optional nonmagnetic metal ion, then this solution is joined containing surfactant with the immiscible organic solvent of water in, make water-in-oil emulsion;
Step c3: the Emulsion that step a3 is obtained or emulsion mix with the Emulsion that step b3 obtains, low whipping speed be under 200-2000rpm condition, stir 60min more than, preferred 80-120min, the microgranule separated, washing makes;
Steps d 3: the microgranule that step c3 is made joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h, separated, washing, obtains embolism materials,
Preferably, above-mentioned emulsion process (double emulsion) comprises the following steps:
Step a3: the sodium alginate aqueous solution that sodium alginate is mixed with to 0.005-0.08g/ml, add optional medicine and optional roentgenopaque material to form mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with the immiscible organic solvent of water in, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b3: preparation is containing the positively charged macromolecular material of 0.005-0.15g/ml magnetic metal ion, optional 0.002-0.131g/ml and the solution of optional 0.002-0.16g/ml nonmagnetic metal ion, then this solution is joined containing surfactant with the immiscible organic solvent of water in, make water-in-oil emulsion;
Step c3: the Emulsion that step a3 is obtained or emulsion mix with the Emulsion that step b3 obtains, low whipping speed be under 200-2000rpm condition, stir 60min more than, preferred 80-120min, the microgranule separated, washing makes;
Steps d 3: the microgranule that step c3 is made joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h, separated, washing, obtains embolism materials.
In above-mentioned emulsion process (double emulsion), also the mixed solution containing cross-linking agent and optional catalyst directly can be added in the mixed liquor (mixed liquor that the Emulsion that the Emulsion being obtained by step a3 or emulsion obtain with step b3 obtains after mixing) of step c3, after reaction, separated, washing, obtain embolism materials.
The present invention further provides above-mentioned embolism materials for the preparation for the treatment of tumor, for example hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma or malignant breast tumor, or vascular malformation or for the purposes of the medicine that stops blooding etc.
Compared with prior art, the present invention adopts the embolism materials that can be detected by MRI of the preparations such as sodium alginate and magnetic metal ion at least to have the following advantages:
1, complication is the principal risk of thromboembolism operation, with dystopy thromboembolism and the harm maximum of backflowing and bringing, adopt embolism materials of the present invention, make doctor monitor in real time the residing position of suppository by MRI, can take measures in time to avoid dystopy thromboembolism and backflowing, thereby improve the efficacy and saferry of embolotherapy; In addition, accurately judgement thromboembolism terminal is the key of thromboembolism successful surgery, thromboembolism not exclusively can cause continuing of symptom or recurrence, inject too much suppository and may cause dystopy thromboembolism, cause normal structure to be damaged, and adopt embolism materials of the present invention to make the doctor can be by MRI direct-detection suppository in endovascular filling situation (degree that whether has suppository to fill and fill in blood vessel) after having injected suppository, judge more exactly thromboembolism terminal, thereby improved the efficacy and saferry of embolotherapy.
2, the embolism materials that can be detected by MRI that prepared by the present invention can be used for clinical treatment and studies: can direct-detection suppository distributed in three dimensions in vivo by MRI, compare various dose, different materials, the thromboembolism result of variable concentrations suppository and the relation between curative effect, thereby be conducive to doctor, update embolization technique, improve the efficacy and safety of embolotherapy.
3, adopt the embolism materials that can be detected by MRI of the present invention, make doctor can in real time, directly monitor suppository present position by MRI in Embolization, estimate effect of embolization and the length to quilt filling vessel segment, whether thromboembolism is fine and close, the trend of vascular embolization etc. is made accurate judgement, is convenient to postoperative check.
4, adopt embolism materials of the present invention to make doctor can detect suppository distribution situation in vivo by MRI after thromboembolism, comprise that whether suppository is even in endovascular distribution, whether the distribution of suppository changes, whether degradable suppository there is degraded etc., thereby be conducive to postoperative evaluation blood vessel by the degree of thromboembolism, for further treating guidance is provided.
5, the rasdiation damage of using the embolism materials that can be detected by MRI of the present invention can avoid patient to be caused because of X-radiological survey X.
6, in embolism materials of the present invention, add after medicine, can make embolotherapy and Drug therapy play synergism, make doctor can utilize MRI directly to monitor and control position and the density of suppository, realize better the target administration function of medicine carrying suppository, make medicine at local sustained release, maintain longer action time, higher local concentration, and reduced the toxic and side effects that medicine causes at other position of whole body.
7, in embolism materials of the present invention, add after roentgenopaque material, embolism materials also can be detected by x-ray, comprise DSA and CT(Computed Tomography, computed tomography) detect, be conducive to doctor and patient and select suitable detection method according to armarium and self-condition.
8, the present invention adopts the embolism materials that can be detected by MRI of the preparations such as sodium alginate and magnetic metal ion, and preparation technology is simple, and cost is low, is applicable to large-scale industrial production, is conducive to clinical expansion and the application of product.
Accompanying drawing explanation
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is the optical microscope photograph of the thromboembolism microgranule of the embodiment of the present invention 4 preparations;
Fig. 2 is the optical microscope photograph of the contrast microgranule of the embodiment of the present invention 4 preparations;
Fig. 3 is the external MRI detected image of thromboembolism microgranule and the contrast microgranule of the embodiment of the present invention 4 preparations;
Fig. 4 is that the thromboembolism microgranule of the embodiment of the present invention 4 preparation is in the subcutaneous MRI detected image of mice;
Fig. 5 is the release curve that carries amycin thromboembolism microgranule of the embodiment of the present invention 9 preparations;
Fig. 6 is the release curve that carries Sorafenib thromboembolism microgranule of the embodiment of the present invention 10 preparations.
The specific embodiment
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is conventional method.In following embodiment, medicine material used, reagent, material etc., if no special instructions, be commercially available purchase product.
embodiment 1the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.005g/ml;
2) under stirring, the sodium alginate aqueous solution that step 1) is made splashes in the solution containing 50g trivalent gadolinium ion (0.045g/ml), after dripping after, continue to stir 120min and react fully, after separated, washing, obtain thromboembolism microgranule.
embodiment 2the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.01g/ml, 5g Bleomycin A5 is joined in sodium alginate aqueous solution, stir, obtain mixed liquor (solution);
2) under stirring, the mixed liquor that step 1) is made splashes in the solution containing 1000g ferric ion (0.12g/ml), 1000g calcium ion (0.12g/ml) and 100g chitosan (0.012g/ml), after dripping, continue to stir 120min and react fully, after separation, washing, obtain thromboembolism microgranule;
3) by step 2) microgranule that makes is soaked in the mixed solution containing 4g formaldehyde and 1g hydrochloric acid, and cross-linking reaction 24h, obtains thromboembolism microgranule after separated, washing.
embodiment 3the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.05g/ml, 0.01g tantalum powder is joined in sodium alginate aqueous solution, stir, obtain mixed liquor (suspension);
2) under stirring, the mixed liquor that step 1) is made splashes in the solution containing 23g ferric ion (0.01g/ml) and 60g chitosan (0.026g/ml), after dripping after, continue to stir 120min and react fully, separated, wash the microgranule making;
3) by step 2) microgranule that makes is soaked in the mixed solution containing 250g formaldehyde and 150g sulphuric acid, and cross-linking reaction 12h, obtains thromboembolism microgranule after separated, washing.
embodiment 4the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to 0.03g/ml sodium alginate aqueous solution;
2) under stirring, the sodium alginate aqueous solution that step 1) is made splashes in the solution containing 6g trivalent holmium ion (0.03g/ml) and 7.5g chitosan (0.038g/ml), after dripping, continue to stir 120min and react fully, the microgranule separated, washing makes;
3) by step 2) microgranule that makes is soaked in the mixed solution containing 160g formaldehyde and 11g hydrochloric acid, and cross-linking reaction 12h, obtains thromboembolism microgranule after separated, washing, and the form of this thromboembolism microgranule under optical microscope is as shown in Figure 1.As can be seen from Figure 1, the thromboembolism microgranule of preparation is substantially spherical in shape, and between granule, dispersibility is better, without bonding and agglomeration.
In addition, adopt do not contain magnetic metal ion with above-mentioned similar method preparation contrast microgranule (being blank thromboembolism microgranule), comprise the following steps:
1) 1g sodium alginate is mixed with to 0.03g/ml sodium alginate aqueous solution;
2) under stirring, the sodium alginate aqueous solution that step 1) is made splashes into containing 1.5g divalent calcium ion (0.0075g/ml, identical with the mole of 6g trivalent holmium ion) and the solution of 7.5g chitosan (0.038g/ml) in, after dripping, continue to stir 120min and react fully, the microgranule separated, washing makes;
3) by 2) microgranule that makes is soaked in the mixed solution containing 160g formaldehyde and 11g hydrochloric acid, cross-linking reaction 12h, separated, washing obtains calcium alginate microgranule, and the form of this calcium alginate microgranule under optical microscope is as shown in Figure 2.
embodiment 5the preparation of thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.07g/ml, 0.01g iodized oil is joined in sodium alginate aqueous solution, stir, 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, low whipping speed is to stir 20min under 200rpm condition, obtains Water-In-Oil oil-in emulsion;
3) to step 2) add the mixed solution containing 0.8g trivalent holmium ion (0.15g/ml), 0.01g calcium ion (0.002g/ml) and 0.7g chitosan (0.131g/ml) in the emulsion that obtains, low whipping speed is to stir 80min under 2000rpm condition, the microgranule separated, washing makes;
4) microgranule step 3) being made is soaked in the mixed solution containing 6g glutaraldehyde and 2g hydrochloric acid, and cross-linking reaction 8h obtains thromboembolism microgranule after separation, washing.
embodiment 6the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to 0.08g/ml sodium alginate aqueous solution, 0.05g tantalum powder is joined in sodium alginate aqueous solution, stir, obtain mixed liquor (suspension);
2) under stirring, the mixed liquor that step 1) is made splashes in the solution containing 0.1g trivalent ytterbium ion (0.005g/ml), 0.01g calcium ion (0.0005g/ml) and 0.2g gelatin (0.01g/ml), after dripping, continue to stir 120min and react fully, the microgranule separated, washing makes;
3) by step 2) microgranule that makes is soaked in the mixed solution containing 80g glutaraldehyde and 6.6g hydrochloric acid, and cross-linking reaction 12h, obtains thromboembolism microgranule after separated, washing.
embodiment 7the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.05g/ml, 0.1g Sutent is joined in sodium alginate aqueous solution, stir, obtain mixed liquor (suspension);
2) under stirring, the mixed liquor that step 1) is made is used static drop generator to splash in the solution containing 2g bivalence barium ions (0.033g/ml), 4.2g trivalent gadolinium ion (0.07g/ml) and 0.3g chitosan (0.005g/ml), after dripping, continue to stir 80min and react fully, the microgranule separated, washing makes;
3) by step 2) microgranule that makes is soaked in the mixed solution containing 260g glutaraldehyde and 17g hydrochloric acid, and cross-linking reaction 12h, obtains thromboembolism microgranule after separated, washing.
embodiment 8the preparation of thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.08g/ml, 2g iodized oil is joined in sodium alginate aqueous solution, stir, 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) add 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) in the emulsion that obtains, under 600rpm mixing speed, continue to stir 100min, the microgranule separated, washing makes;
4) microgranule step 3) being made is soaked in the mixed solution containing 100g formaldehyde and 6.3g hydrochloric acid, and cross-linking reaction 24h obtains thromboembolism microgranule after separation, washing.
embodiment 9the preparation of medicine carrying thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.01g/ml, 0.3g amycin is joined in sodium alginate aqueous solution, stir, obtain mixed liquor (solution);
2) mixed liquor of step 1) is joined in the mixed liquor containing 50g sorbester p17 and 400g cyclohexane extraction, under 1700rpm mixing speed, stir 30min, obtain water-in-oil emulsion;
3) to step 2) add the mixed solution containing 12g trivalent holmium ion (0.12g/ml) and 1g chitosan (0.01g/ml) in the Emulsion that obtains, under 200rpm mixing speed, stir 120min, the microgranule separated, washing makes;
4) microgranule step 3) being made is soaked in the solution containing 250g glutaraldehyde, and cross-linking reaction 12h obtains thromboembolism microgranule after separation, washing;
embodiment 10the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.03g/ml, 0.05g Sorafenib is joined in sodium alginate aqueous solution, stir, obtain mixed liquor (solution);
2) under stirring, the mixed liquor that step 1) is made splashes in the solution containing 3g trivalent gadolinium ion (0.008g/ml), 0.3g calcium ion (0.0008g/ml) and 6.7g chitosan (0.018g/ml), after dripping, continue to stir 120min and react fully, the microsphere separated, washing makes;
3) by step 2) microgranule that makes is soaked in the mixed solution containing 350g formaldehyde and 100g hydrochloric acid, and cross-linking reaction 12h, obtains thromboembolism microgranule after separated, washing.
embodiment 11the preparation of thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.005g/ml, 5g iofendylate is joined in sodium alginate aqueous solution, stir, 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) add the mixed solution containing 18g trivalent holmium ion (0.05g/ml), 20g calcium ion (0.056g/ml) and 2g chitosan (0.006g/ml) in the emulsion that obtains, under 400rpm mixing speed, continue to stir 100min, the microgranule separated, washing makes;
4) microgranule step 3) being made is soaked in the mixed solution containing 350g formaldehyde and 150g hydrochloric acid, and cross-linking reaction 12h obtains thromboembolism microgranule after separation, washing.
embodiment 12the preparation of thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to 0.007g/ml sodium alginate aqueous solution, 0.5g tantalum powder and 0.05g cisplatin are joined in sodium alginate aqueous solution, stir, 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) add in the mixed solution containing 20g trivalent holmium ion (0.12g/ml), 3g calcium ion (0.018g/ml) and 0.5g gelatin (0.003g/ml) in the Emulsion that obtains; under 1500rpm mixing speed, continue to stir 100min, the microgranule separated, washing makes;
4) microgranule step 3) being made is soaked in the mixed solution containing 4g glutaraldehyde and 1g hydrochloric acid, and cross-linking reaction 15h obtains thromboembolism microgranule after separation, washing.
embodiment 13the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with 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, the mixed liquor that step 1) is made splashes in the solution containing 5g trivalent gadolinium ion (0.006g/ml), after dripping after, continue to stir 120min and react fully, the microgranule separated, washing makes;
3) by step 2) microgranule that makes is soaked in the mixed solution containing 6g glutaraldehyde and 2g hydrochloric acid, and cross-linking reaction 20h, obtains thromboembolism microgranule after separated, washing.
embodiment 14the preparation of thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to 0.02g/ml sodium alginate aqueous solution, 0.05g tantalum powder and 5g cisplatin are joined in sodium alginate aqueous solution, stir, 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) add in the solution containing 6g trivalent holmium ion (0.09g/ml) in the Emulsion that obtains, under 1000rpm mixing speed, continue to stir 100min, the microgranule separated, washing makes;
4) microgranule step 3) being made is soaked in the solution containing 120g glutaraldehyde, and cross-linking reaction 15h obtains thromboembolism microgranule after separation, washing.
embodiment 15the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with 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, the mixed liquor that step 1) is made splashes in the solution containing 210g trivalent gadolinium ion (0.05g/ml), after dripping after, continue to stir 90min and react fully, the microgranule separated, washing makes;
3) by step 2) microgranule that makes is soaked in the solution containing 100g formaldehyde, and cross-linking reaction 8h, obtains thromboembolism microgranule after separated, washing.
embodiment 16the preparation of thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to 0.009g/ml sodium alginate aqueous solution, 0.1g Sorafenib is joined in sodium alginate aqueous solution, stir, 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) preparation, containing the solution of 8g trivalent holmium ion (0.09g/ml), is joined in the mixed liquor containing 7g sorbester p17 and 200g liquid paraffin, stirs, and obtains water-in-oil emulsion;
4) by step 2) and the Emulsion that obtains of step 3) mix, low whipping speed is under 1700rpm condition, to continue to stir 100min, the microgranule separated, washing makes.
embodiment 17the preparation of thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to 0.05g/ml sodium alginate aqueous solution, 1g lignocaine is joined in sodium alginate aqueous solution, stir, 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) add in the solution containing 0.1g trivalent holmium ion (0.005g/ml) in the Emulsion that obtains, under 900rpm mixing speed, continue to stir 100min, the microgranule separated, washing makes;
4) microgranule step 3) being made is soaked in the solution containing 60g glutaraldehyde, and cross-linking reaction 15h obtains thromboembolism microgranule after separation, washing.
embodiment 18the preparation of thromboembolism microgranule
The present embodiment adopts dropping preparation method to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to 0.06g/ml sodium alginate aqueous solution, 0.6g Sorafenib and 1g tantalum powder are joined in sodium alginate aqueous solution, stir, obtain mixed liquor (suspension);
2) under stirring, the mixed liquor that step 1) is made splashes in the solution containing 20g trivalent gadolinium ion (0.12g/ml), 20g calcium ion (0.12g/ml) and 20g chitosan (0.12g/ml), after dripping, continue to stir 100min and react fully, the microsphere separated, washing makes;
3) by step 2) microgranule that makes is soaked in the mixed solution containing 40g formaldehyde and 45g hydrochloric acid, and cross-linking reaction 15h, obtains thromboembolism microgranule after separated, washing.
embodiment 19the preparation of thromboembolism microgranule
The present embodiment adopts emulsion process to prepare thromboembolism microgranule, comprises the following steps:
1) 1g sodium alginate is mixed with to the sodium alginate aqueous solution of 0.03g/ml, 0.6g Sorafenib and 1g iofendylate are joined in sodium alginate aqueous solution, stir, 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) preparation, containing the solution of 1g trivalent holmium ion (0.016g/ml), 10g calcium ion (0.16g/ml) and 0.1g gelatin (0.002g/ml), joins solution in the mixed liquor containing 25g sorbester p17 and 60g liquid paraffin, stirs, and obtains water-in-oil emulsion;
4) by step 2) and the Emulsion that obtains of step 3) mix, low whipping speed is under 1200rpm condition, to continue to stir 90min, the microgranule separated, washing makes;
5) microgranule step 4) being made is added in the mixed solution containing 180g formaldehyde and 40g hydrochloric acid, and after reaction 20h, separated, washing, obtains embolism materials.
the external MRI of thromboembolism microgranule detects
The thromboembolism microgranule of embodiment 4 preparations (containing magnetic metal ion) and contrast microgranule (not containing magnetic metal ion) are carried out to MRI vitro detection.In culture dish, add 1 centimetre of high agar solution, after its cooled and solidified is agaropectin, thromboembolism microgranule (containing magnetic metal ion) and contrast microgranule (not containing magnetic metal ion) are placed into respectively on agaropectin, repave 1 centimetre of high agaropectin of one deck.Sample in agaropectin is carried out to magnetic resonance detection, and nuclear magnetic resonance result as shown in Figure 3.Fig. 3 has shown the thromboembolism microgranule (upper strata containing magnetic metal ion, black) with containing magnetic metal ion, do not contrast microgranule (lower floor, white) external MRI detected image (number of two-layer microgranule is respectively 1,2,3,4,5 from left to right), as can be seen from Figure 3, the present invention adopts thromboembolism microgranule prepared by sodium alginate and magnetic metal ion directly clearly to be detected by MRI, and the contrast microgranule containing magnetic metal ion can not detected by MRI.
thromboembolism microgranule detects at the subcutaneous MRI of mice
From the thromboembolism microgranule of embodiment 4 preparations, sieve out the microgranule of 100-300 μ m, by the carboxymethylcellulose sodium solution of microgranule suspendible to 1%, injection mice is subcutaneous.Mice is placed under 3T MRI and is scanned, and testing result as shown in Figure 4.Fig. 4 shows thromboembolism microgranule in the subcutaneous MRI detected image of mice, and the external white bright spot of Fig. 4 small mouse is vitamin E capsule, and white arrow indicates injection site, result demonstration, and the thromboembolism microgranule subcutaneous mice can be detected by MRI.
the release experiment of medicine carrying thromboembolism microgranule
Adopt T shape pipe method to measure the release in vitro of carrying amycin thromboembolism microgranule of embodiment 9 preparations.Experimentation is as follows: in T-shaped pipe, add the phosphate buffer of 200ml pH7.4 as release medium, buffer mobility is 50ml/min, and bath temperature is 37 ℃.1ml is carried to the bottom that amycin thromboembolism microgranule is placed in T shape pipe, in 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, take out respectively 5ml release medium and supply immediately isothermal, isopyknic fresh release medium, under 233nm wavelength, measuring absorbance, according to standard curve, calculating release amount.Carry the release curve of amycin thromboembolism microgranule as shown in Figure 5.As seen from Figure 5, carry amycin thromboembolism microgranule very fast in front 6h rate of release, during 6h, cumulative release approximately 75%, and during 24h, cumulative release approximately 89%.
Adopt T shape pipe method to measure the release in vitro of carrying Sorafenib thromboembolism microgranule of embodiment 10 preparations.Experimentation is as follows: in T-shaped pipe, add the phosphate buffer of 200ml pH7.4 as release medium, buffer mobility is 50ml/min, and bath temperature is 37 ℃.1ml is carried to the bottom that Sorafenib thromboembolism microgranule is placed in T shape pipe, in 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, take out respectively 5ml release medium and supply immediately isothermal, isopyknic fresh release medium, under 265nm wavelength, measuring absorbance, according to standard curve, calculating release amount.Carry the release curve of Sorafenib thromboembolism microgranule as shown in Figure 6.As seen from Figure 6, carry Sorafenib thromboembolism microgranule very fast in front 4h rate of release, during 4h, cumulative release approximately 60%, and during 24h, cumulative release approximately 80%.
Specific description of embodiments of the present invention above does not limit the present invention, and those skilled in the art can make according to the present invention various changes or distortion, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (11)
1. an embolism materials, it is made by reactant feed, and described reactant feed comprises: the sodium alginate of 1 weight portion and magnetic metal ion more than 0.1 weight portion, wherein, sodium alginate and magnetic metal ion form coordination compound.
2. embolism materials according to claim 1, is characterized in that, described reactant feed further comprises 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 that is comprised of cross-linking agent and catalyst;
Preferably, described reactant feed further comprises one or more in following material: 0.1-100 weight portion macromolecular material, the roentgenopaque material of 0.01-5 weight portion, nonmagnetic metal ion more than 0.01 weight portion, 4-500 weight portion auxiliary agent or 0.05-5 weight portion medicine.
3. embolism materials according to claim 1 and 2, is characterized in that, described embolism materials adopts emulsion process preparation, and described reactant feed comprises:
Preferably, described reactant feed comprises:
4. embolism materials according to claim 1 and 2, is characterized in that, described embolism materials adopts dropping preparation method preparation, and described reactant feed comprises:
More than sodium alginate 1 weight portion 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 of catalyst 1-150 weight portion weight portion
More than cross-linking agent 4-350 weight portion nonmagnetic metal ion 0.01 weight portion
Preferably, described reactant feed comprises:
Sodium alginate 1 weight portion 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 of catalyst 2-100 weight portion weight portion
Cross-linking agent 6-250 weight portion nonmagnetic metal ion 0.3-1000 weight portion.
5. according to the embolism materials described in any one in claim 1 to 4, it is characterized in that, described embolism materials is that particle diameter is the microgranule of 1-2000 μ m, and preferable particle size is the microsphere of 1-2000 μ m.
6. according to the embolism materials described in any one in claim 1 to 5, it is characterized in that one or more in described magnetic metal ion chosen from Fe, manganese, cobalt, nickel, holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium ion;
Preferably, described nonmagnetic metal ion is selected from one or more in calcium, aluminum, barium, lead, cadmium, copper, strontium or zinc ion;
Preferably, described positively charged macromolecular material is biocompatible polymer material, preferably one or both in chitosan or gelatin;
Preferably, described catalyst is selected from one or more in hydrochloric acid, sulphuric acid, phosphoric acid or acetic acid;
Preferably, described cross-linking agent is selected from one or more in formaldehyde, acetaldehyde, Biformyl, butyraldehyde, boric acid, Borax, glutaraldehyde, hexandial or genipin;
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;
Preferably, described antitumor drug is selected from one or more in amycin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel, Docetaxel, 5-fluorouracil, Bleomycin A5, Sutent, Sorafenib, gefitinib, imatinib, PTK787 or its salt;
Preferably, described local anaesthesia medicine is selected from one or more in procaine, chloroprocaine, hydroxyprocaine, tetracaine, parethoxycaine, empty Tuo Kayin, dimethocaine, lignocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, supernatural power caine, quinisocaine, phenacaine or its salt;
Preferably, described antipyretic-antalgic anti-inflammatory agent thing is selected from one or more in aspirin, magnesium salicylate, sodium salicylate, choline magnesium trisalicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, fenoprofen, naproxen, nabumetone, piroxicam, Phenylbutazone, acetaminophen, diclofenac, venlofen, ketone ibuprofen, ketorolac, four clofenamic acides, sulindac or tolmetin;
Preferably, described antibiotic medicine is selected from one or more in penicillin, oxacillin sodium, ampicillin, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid, sulbactam, oxytetracycline, tetracycline, demeclocycline, streptomycin, kanamycin A, gentamycin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribostamycin, bekanamycin, framycetin, paromomycin, erythromycin, Roxithromycin, clarithromycin, azithromycin, chloromycetin, ciclosporin, lincomycin or its salt;
Preferably, described surfactant be selected from spans surfactant or the mixture that formed by spans surfactant and Tweens surfactant in one or both;
Preferably, described organic solvent is and the immiscible organic solvent of water; Preferably, described organic solvent is selected from one or more in mineral oil, vegetable oil, silicone oil, alkene, alcohol, aldehyde, amine, ether or ketone, preferred liquid paraffin, isobutyltrimethylmethane. or cyclohexane extraction.
7. according to the preparation method of the embolism materials described in any one in claim 1 to 6, described preparation method comprises the following steps:
Step a: sodium alginate is mixed with to sodium alginate aqueous solution;
Step b: by the sodium alginate soln in step a and the solution reaction that contains magnetic metal ion, obtain thromboembolism microgranule,
Preferably, described preparation method further comprises:
Step c: the thromboembolism microgranule that step b is obtained joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, separated, washing, obtains embolism materials.
8. preparation method according to claim 7, is characterized in that, described preparation method is dropping preparation method, comprises the following steps:
Step a1: sodium alginate is mixed with to sodium alginate aqueous solution, adds optional medicine and optional roentgenopaque material to form mixed liquor;
Step b1: under stirring, sodium alginate soln in step a1 or mixed liquor are splashed in the solution containing magnetic metal ion, optional positively charged macromolecular material and optional nonmagnetic metal ion, after dripping, more than stirring 60min, preferred 80-120min, the microgranule separated, washing makes; Preferably, use static drop generator that the sodium alginate soln in step a1 or mixed liquor are splashed in the solution containing magnetic metal ion, optional positively charged macromolecular material and optional nonmagnetic metal ion;
Step c1: the microgranule that step b1 is obtained joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h hour, separated, washing, obtains embolism materials,
Preferably, described preparation method comprises the following steps:
Step a1: sodium alginate is mixed with to the sodium alginate aqueous solution of 0.005-0.08g/ml, adds optional medicine and optional roentgenopaque material to form mixed liquor;
Step b1: under stirring, sodium alginate soln in step a1 or mixed liquor are splashed in the solution containing the positively charged macromolecular material of 0.005-0.12g/ml magnetic metal ion, optional 0.005-0.12g/ml and optional 0.0005-0.12g/ml nonmagnetic metal ion, after dripping, more than stirring 60min, preferred 80-120min, the microgranule separated, washing makes; Preferably, use static drop generator that the sodium alginate soln in step a1 or mixed liquor are splashed in the solution containing the positively charged macromolecular material of 0.005-0.12g/ml magnetic metal ion, optional 0.005-0.12g/ml and optional 0.0005-0.12g/ml nonmagnetic metal ion;
Step c1: the microgranule that step b1 is obtained joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h hour, separated, washing, obtains embolism materials.
9. preparation method according to claim 7, is characterized in that, described preparation method is emulsion process, comprises the following steps:
Step a2: sodium alginate is mixed with to sodium alginate aqueous solution, add optional medicine and optional roentgenopaque material to form mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant and with the mixed liquor of the immiscible organic solvent of water in, 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 Emulsion obtaining to step a2 or emulsion in the solution containing magnetic metal ion, optional positively charged macromolecular material and optional nonmagnetic metal ion, low whipping speed be under 200-2000rpm condition, stir 60min more than, preferred 80-120min, the microgranule separated, washing makes;
Step c2: the microgranule that step b2 is made joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h, separated, washing, obtains embolism materials;
Preferably, described preparation method comprises the following steps:
Step a2: the sodium alginate aqueous solution that sodium alginate is mixed with to 0.005-0.08g/ml, add optional medicine and optional roentgenopaque material to form mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with the immiscible organic solvent of water in, 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 Emulsion obtaining to step a2 or emulsion in the solution containing the positively charged macromolecular material of 0.005-0.15g/ml magnetic metal ion, optional 0.002-0.131g/ml and optional 0.002-0.16g/ml nonmagnetic metal ion, low whipping speed be under 200-2000rpm condition, stir 60min more than, preferred 80-120min, the microgranule separated, washing makes;
Step c2: the microgranule that step b2 is made joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h, separated, washing, obtains embolism materials.
10. preparation method according to claim 7, is characterized in that, described preparation method is emulsion process, comprises the following steps:
Step a3: sodium alginate is mixed with to sodium alginate aqueous solution, add optional medicine and optional roentgenopaque material to form mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with the immiscible organic solvent of water in, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b3: preparation is containing the solution of magnetic metal ion, optional positively charged macromolecular material and optional nonmagnetic metal ion, then this solution is joined containing surfactant with the immiscible organic solvent of water in, make water-in-oil emulsion;
Step c3: the Emulsion that step a3 is obtained or emulsion mix with the Emulsion that step b3 obtains, low whipping speed be under 200-2000rpm condition, stir 60min more than, preferred 80-120min, the microgranule separated, washing makes;
Steps d 3: the microgranule that step c3 is made joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h, separated, washing, obtains embolism materials,
Preferably, described preparation method is emulsion process, comprises the following steps:
Step a3: the sodium alginate aqueous solution that sodium alginate is mixed with to 0.005-0.08g/ml, add optional medicine and optional roentgenopaque material to form mixed liquor, then sodium alginate soln or mixed liquor are joined containing surfactant with the immiscible organic solvent of water in, under 200-2000rpm mixing speed, stir 10-40min, obtain water-in-oil emulsion or Water-In-Oil oil-in emulsion;
Step b3: preparation is containing the positively charged macromolecular material of 0.005-0.15g/ml magnetic metal ion, optional 0.002-0.131g/ml and the solution of optional 0.002-0.16g/ml nonmagnetic metal ion, then this solution is joined containing surfactant with the immiscible organic solvent of water in, make water-in-oil emulsion;
Step c3: the Emulsion that step a3 is obtained or emulsion mix with the Emulsion that step b3 obtains, low whipping speed be under 200-2000rpm condition, stir 60min more than, preferred 80-120min, the microgranule separated, washing makes;
Steps d 3: the microgranule that step c3 is made joins in the mixed solution containing cross-linking agent and optional catalyst, after reaction, after preferred reaction 8-24h, separated, washing, obtains embolism materials.
11. according to the embolism materials described in any one in claim 1 to 6 for the preparation for the treatment of tumor, for example hepatocarcinoma, colorectal cancer hepatic metastases, renal carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, hysteromyoma or malignant breast tumor, or vascular malformation or for the purposes of the medicine that stops blooding.
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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 |