CN117618631A - 显影栓塞微球及其制备方法 - Google Patents
显影栓塞微球及其制备方法 Download PDFInfo
- Publication number
- CN117618631A CN117618631A CN202311685221.2A CN202311685221A CN117618631A CN 117618631 A CN117618631 A CN 117618631A CN 202311685221 A CN202311685221 A CN 202311685221A CN 117618631 A CN117618631 A CN 117618631A
- Authority
- CN
- China
- Prior art keywords
- embolic
- microsphere
- developing
- contrast agent
- embolic microsphere
- 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.)
- Pending
Links
- 239000004005 microsphere Substances 0.000 title claims abstract description 84
- 208000005189 Embolism Diseases 0.000 title abstract description 26
- 238000002360 preparation method Methods 0.000 title description 9
- 230000003073 embolic effect Effects 0.000 claims abstract description 61
- 239000002872 contrast media Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 18
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims abstract description 13
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 12
- 239000011630 iodine Substances 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 10
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 7
- 229960001025 iohexol Drugs 0.000 claims description 7
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- DVKJHBMWWAPEIU-UHFFFAOYSA-N toluene 2,4-diisocyanate Chemical compound CC1=CC=C(N=C=O)C=C1N=C=O DVKJHBMWWAPEIU-UHFFFAOYSA-N 0.000 claims description 4
- 229920001661 Chitosan Polymers 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 125000005442 diisocyanate group Chemical group 0.000 claims description 3
- -1 iobiziol Chemical compound 0.000 claims description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- RTTZISZSHSCFRH-UHFFFAOYSA-N 1,3-bis(isocyanatomethyl)benzene Chemical compound O=C=NCC1=CC=CC(CN=C=O)=C1 RTTZISZSHSCFRH-UHFFFAOYSA-N 0.000 claims description 2
- FWWWRCRHNMOYQY-UHFFFAOYSA-N 1,5-diisocyanato-2,4-dimethylbenzene Chemical compound CC1=CC(C)=C(N=C=O)C=C1N=C=O FWWWRCRHNMOYQY-UHFFFAOYSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- XUHXFSYUBXNTHU-UHFFFAOYSA-N Iotrolan Chemical compound IC=1C(C(=O)NC(CO)C(O)CO)=C(I)C(C(=O)NC(CO)C(O)CO)=C(I)C=1N(C)C(=O)CC(=O)N(C)C1=C(I)C(C(=O)NC(CO)C(O)CO)=C(I)C(C(=O)NC(CO)C(O)CO)=C1I XUHXFSYUBXNTHU-UHFFFAOYSA-N 0.000 claims description 2
- AMDBBAQNWSUWGN-UHFFFAOYSA-N Ioversol Chemical compound OCCN(C(=O)CO)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I AMDBBAQNWSUWGN-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 229920002674 hyaluronan Polymers 0.000 claims description 2
- 229960003160 hyaluronic acid Drugs 0.000 claims description 2
- 229960004359 iodixanol Drugs 0.000 claims description 2
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 claims description 2
- 229960002603 iopromide Drugs 0.000 claims description 2
- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 claims description 2
- 229960003182 iotrolan Drugs 0.000 claims description 2
- 229960004537 ioversol Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 239000004632 polycaprolactone Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 239000004626 polylactic acid Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 7
- 208000014018 liver neoplasm Diseases 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000003431 cross linking reagent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 238000012412 chemical coupling Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 150000000921 Gadolinium Chemical class 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000010102 embolization Effects 0.000 description 1
- 238000010556 emulsion polymerization method Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000008424 iodobenzenes Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-UHFFFAOYSA-N 0.000 description 1
- 239000002331 radioactive microsphere Substances 0.000 description 1
- 238000011297 radiofrequency ablation treatment Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明公开了一种显影栓塞微球,在栓塞微球的表面,通过异氰酸酯基团接枝有含碘造影剂。还公开了其制备方法。本发明提供的显影栓塞微球,具有X射线吸收功能,可在术中直接观察栓塞剂位置、判断栓塞终点,降低异位栓塞的风险。
Description
技术领域
本发明涉及一种显影栓塞微球及其制备方法,属于医疗器械技术领域。
背景技术
在我国疾病死亡率排名中,肿瘤一直位于前列,有关肿瘤诊断和治疗的研究受到了广泛关注。其中肝癌作为发病率最高的癌症类型之一,据统计,2021年全球新发肝癌90.56万例,我国新发肝癌46.6万例,占全球的55%。肝癌死亡率高,已成为癌症死亡的第三大主要原因,严重威胁国民生命和健康。目前,对于肝癌早期治疗的常用方法有手术切除、射频消融治疗、化疗和放疗等。但大多数肝癌患者确诊时已是中晚期,据统计只有20%~35%的患者能够接受切除手术。经导管动脉栓塞治疗(TAE)被认为是中晚期肝癌患者姑息性治疗的首选方法,即在影像设备的监视下,通过导管将栓塞材料注入肿瘤组织的供血动脉血管,既阻断血养供给“饿死”肿瘤,抑制肿瘤生长,还能在局部释放高浓度的放化疗药物杀死肿瘤,具有微创、安全、靶向等优点,既提高了治疗效率,也降低了全身毒性,已成为非外科手术治疗肝癌的首选方法。
可用于栓塞治疗的栓塞材料有很多,早期有明胶海绵颗粒、碘化油等,随着材料的发展和进步,微球由于其球形独有的流动性成为了栓塞材料的首要选择。微球中常用的栓塞材料包括聚乙烯醇(PVA)、聚乳酸-羟基乙酸共聚物(PLGA)、海藻酸钙以及壳聚糖等,这些材料具有良好的生物相容性,材料无毒、价格低廉、来源丰富,因而在生物医学领域得到了广泛的应用。目前市场上已有多种不同功能的栓塞微球,如空白微球、载药微球、放射性微球、可降解微球等。其中,载药微球具有可以加载多种药物的优势,同时发挥栓塞和药物的作用,如恒瑞公司的Callispheres、国外的DC Bead、Embosphere、Hepasphere等,具有广阔的应用前景。然而,在临床使用中,为了实现栓塞微球的可追踪性,通常需要栓塞微球能够具有X射线可吸收性(造影能力),同时,市面上的大部分微球自身不能显影,在手术中难以精确定位,一定程度上影响了栓塞效果的考察。因此,开发制备能自身显像的栓塞微球具有重要研究意义和市场价值。
中国发明专利CN115845117A公开了一种栓塞剂,将凝胶组分与无机成分混合均匀,得到混合凝胶,同时加入微球及显影剂混合均匀,得到的栓塞微球有显影效果,使用中无需额外添加显影剂;中国发明专利CN115770321A公开了一种栓塞微球及其制备方法,将水相溶液与油相溶液混合形成水包油的正向悬浮聚合体系,致孔剂为甲苯、液蜡和正庚烷的混合试剂,将微球与硫酸钠溶液搅拌分散于水中,加入氯化钡溶液搅拌分散,得到负载有硫酸钡的显影栓塞微球。上述技术通过造影剂与微球物理混合的方法,有一定的造影剂溶出风险,可能影响治疗中及预后效果。
中国发明专利CN115590824A公开了一种带显影剂的聚乙烯醇栓塞微球及其制备方法和应用,首先将二乙基三胺五乙酸二酸酐与甲基丙烯酸-2-氨基乙基酯混合发生酰胺化,反应生成接有两个甲基丙烯酸-2-氨基乙基酯的DTPA,再与钆盐发生螯合反应,制备带显影元素的交联剂,再通过乳液聚合法或微流控法制备聚乙烯醇微球并用上述交联剂进行交联,制作出MRI下带有显影效果与载药能力的聚乙烯醇栓塞微球。该技术为磁共振显影,不属于X射线显影技术。
中国发明专利CN115590824A公开了一种不透射线显影栓塞微球及其制备方法,通过共价键偶联的含碘的显影剂、聚乙烯醇微球和带有磺酸基的水溶性聚合物的聚合物微球,得到结构更加稳定的不透射线显影栓塞微球;中国发明专利CN115487342A公开了一种自显影可吸收栓塞微球及其制备方法,通过化学键合的方式,将可显影的碘代苯化合物引入明胶海绵栓塞微球中,提供了一种不透X射线的自显影可吸收栓塞微球;中国发明专利CN114377190A公开了一种可显影的栓塞微球及其制备方法,将具有生物降解性的功能化大分子通过引发剂、交联剂以及造影剂交联聚合形成的栓塞微球,其在X射线的照射下能够显影;中国发明专利CN114057600A公开了一种可X射线显影分子、载药栓塞微球及其制备方法,通过由含氨基或羟基的碘苯类衍生物与丙烯酸酐反应得到带有双键的可X射线显影的分子,制备可X射线显影的载药栓塞微球。上述技术通过自行设计或制备含碘化合物应用于栓塞微球,不涉及碘海醇等商用造影剂的直接化学偶联或表面修饰。
以碘海醇为代表的造影剂,是一类商品化的鞘内注射用X射线显影剂,广泛用于心血管、动静脉、胆道、尿路、颅内及椎管等造影检查及介入手术,具有较低的渗透压和毒性。与现有专利技术不同,本发明针对栓塞微球在临床使用中的关注点和痛点,提出一种简易高效的方法,用于栓塞微球的造影剂偶联修饰。具体地,通过二异氰酸酯类试剂对栓塞微球进行表面修饰,将栓塞微球表面共价偶联异氰酸酯基团,并进一步与造影剂上的羟基进行共价反应,将造影剂共价修饰在栓塞微球表面。赋予在其使用过程中的显影性能,进而避免或减少栓塞微球在使用过程中的异位栓塞的风险。更具体地,是提供一种在栓塞微球上共价偶联X射线显影剂的方法及相关工艺。
发明内容
本发明的目的是利用表面接枝造影剂的方法,实现可显影的栓塞微球。
本发明的目的通过以下技术方案实现:
一种显影栓塞微球,在栓塞微球的表面,通过异氰酸酯基团接枝有含碘造影剂。
优选的,异氰酸酯基团与含碘造影剂的羟基进行化学偶联。
优选的,异氰酸酯基团来源于甲苯-2,4-二异氰酸酯、间苯二甲基二异氰酸酯或1,3-苯二异氰酸酯。
优选的,所述含碘造影剂从碘普罗胺、泛影葡胺、碘苯六醇、碘曲伦、碘比醇,碘克沙醇、碘佛醇、碘海醇中选择。
优选的,栓塞微球的材质为聚乳酸、聚己内酯、聚乙醇酸、聚乙二醇、聚丙烯酸酯、聚乙烯醇及上述共聚物、纤维素、海藻酸及其盐类、透明质酸及其盐类、壳聚糖、葡聚糖或明胶。
本发明还公开了上述的显影栓塞微球的制备方法,其步骤包括:
(1)将栓塞微球浸没在二异氰酸酯类试剂的溶液中,在催化剂的作用下进行接枝反应,将异氰酸酯基团通过共价反应的方式修饰在栓塞微球表面;
(2)将修饰有异氰酸酯基团的栓塞微球浸没在含碘造影剂的溶液中,在催化剂的作用下进行接枝反应,异氰酸酯基团与含碘造影剂的羟基进行化学偶联,获得表面共价修饰造影剂的栓塞微球。
优选的,步骤(1)和(2)中的催化剂均为三乙胺。
优选的,步骤(1)中的溶剂为有机溶剂,从N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、甲苯、氯仿中选择;步骤(2)中的溶剂为水。
优选的,步骤(1)的反应温度为40~90℃,反应时间为0.5~4h。
优选的,步骤(2)的反应温度为40~90℃,反应时间为0.5~4h。
有益效果:本发明提供的显影栓塞微球,具有X射线吸收功能,可在术中直接观察栓塞剂位置、判断栓塞终点,降低异位栓塞的风险。
附图说明
图1为碘海醇(iohexol)的化学结构式。
图2为显影栓塞微球的制备工艺示意图。
图3为显影栓塞微球的结构示意图。
具体实施方法:
下面结合实施例对本发明作进一步的说明,但实施例的描述不对本发明的保护范围产生任何限制。
除非另有定义,本文所使用的所有的技术术语和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同,本文在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
下列实施例中所用的物质或仪器,如果未进行特殊说明的话,均可以从常规的商用渠道获取。
实施例1
取10mL栓塞微球,材质为聚乙烯醇(PVA),经乙醇、去离子水反复超声清洗三次后,将栓塞微球取出并浸入20mL甲苯-2,4-二异氰酸酯(TDI)的甲苯溶液中(体积浓度10%),加入三乙胺作催化剂(体积浓度5%),60℃下处理1h进行接枝反应,随后将栓塞微球取出并用甲苯反复冲洗3次后,置于20mL碘海醇(化学结构式如图1所示)的水溶液中,浓度为10wt%,三乙胺作催化剂,体积浓度为5%,40℃下,处理2h。反应结束后将栓塞微球取出并纯水冲洗3次,置于纯水中浸没或干燥保存。得到的具有显影性能的栓塞微球,其特征是具有X射线吸收功能。反应过程如图2所示,制得的栓塞微球结构如图3所示。
上述具有显影功能的栓塞微球,在X射线的照射下能够显影,可实现栓塞微球在人体内的探测和示踪,有利于栓塞治疗后栓塞程度及范围的追踪。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围,凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种显影栓塞微球,其特征在于在栓塞微球的表面,通过异氰酸酯基团接枝有含碘造影剂。
2.根据权利要求1所述的显影栓塞微球,其特征在于异氰酸酯基团与含碘造影剂的羟基进行化学偶联。
3.根据权利要求1所述的显影栓塞微球,其特征在于异氰酸酯基团来源于甲苯-2,4-二异氰酸酯、间苯二甲基二异氰酸酯或1,3-苯二异氰酸酯。
4.根据权利要求1所述的显影栓塞微球,其特征在于所述含碘造影剂从碘普罗胺、泛影葡胺、碘苯六醇、碘曲伦、碘比醇,碘克沙醇、碘佛醇、碘海醇中选择。
5.根据权利要求1所述的显影栓塞微球,其特征在于栓塞微球的材质为聚乳酸、聚己内酯、聚乙醇酸、聚乙二醇、聚丙烯酸酯、聚乙烯醇及上述共聚物、纤维素、海藻酸及其盐类、透明质酸及其盐类、壳聚糖、葡聚糖或明胶。
6.权利要求1-5中任一项所述的显影栓塞微球的制备方法,其特征在于其步骤包括:
(1)将栓塞微球浸没在二异氰酸酯类试剂的溶液中,在催化剂的作用下进行接枝反应,获得修饰有异氰酸酯基团的栓塞微球;
(2)将修饰有异氰酸酯基团的栓塞微球浸没在含碘造影剂的溶液中,在催化剂的作用下进行接枝反应,获得表面共价修饰造影剂的栓塞微球。
7.根据权利要求6所述的制备方法,其特征在于步骤(1)和(2)中的催化剂均为三乙胺。
8.根据权利要求7所述的制备方法,其特征在于步骤(1)中的溶剂为有机溶剂,从N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、甲苯、氯仿中选择;
步骤(2)中的溶剂为水。
9.根据权利要求7所述的制备方法,其特征在于步骤(1)的反应温度为40~90℃,反应时间为0.5~4h。
10.根据权利要求7所述的制备方法,其特征在于步骤(2)的反应温度为40~90℃,反应时间为0.5~4h。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311685221.2A CN117618631A (zh) | 2023-12-11 | 2023-12-11 | 显影栓塞微球及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311685221.2A CN117618631A (zh) | 2023-12-11 | 2023-12-11 | 显影栓塞微球及其制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117618631A true CN117618631A (zh) | 2024-03-01 |
Family
ID=90028745
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311685221.2A Pending CN117618631A (zh) | 2023-12-11 | 2023-12-11 | 显影栓塞微球及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117618631A (zh) |
-
2023
- 2023-12-11 CN CN202311685221.2A patent/CN117618631A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11998563B2 (en) | Polymeric treatment compositions | |
US10543295B2 (en) | Particles | |
CN106822983B (zh) | 一种用于微创介入疗法***疾病的可显影栓塞微球及其制备方法 | |
JP6058056B2 (ja) | 非分解性、低膨潤性、水溶性、放射線不透過性のヒドロゲル | |
CN111569144A (zh) | 具有显影功能的可载药栓塞微球及其制备方法 | |
CN105517580A (zh) | 可成像栓塞微球 | |
CN102232098A (zh) | 用于治疗血管栓塞形成的微球 | |
CN109021169A (zh) | 一种海藻酸钠聚合物、新型海藻酸钠血管栓塞化疗组合物及其制备方法和用途 | |
CN114057600B (zh) | 一种可x射线显影分子、载药栓塞微球及其制备方法 | |
CN113018463A (zh) | 一种含放射性核素的医用天然高分子微球及其制备方法和用途 | |
CN114917399A (zh) | 三种高分子微球及其制备方法和应用 | |
WO2017143277A1 (en) | Microspheres containing therapeutic agents and related methods of use | |
CN117618631A (zh) | 显影栓塞微球及其制备方法 | |
US20230032358A1 (en) | Embolization agent | |
CN115141319A (zh) | 工程化放射性聚合物微球及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |