CN115671370B - Embolic microsphere capable of slowly releasing medicine and preparation method thereof - Google Patents
Embolic microsphere capable of slowly releasing medicine and preparation method thereof Download PDFInfo
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- CN115671370B CN115671370B CN202211426597.7A CN202211426597A CN115671370B CN 115671370 B CN115671370 B CN 115671370B CN 202211426597 A CN202211426597 A CN 202211426597A CN 115671370 B CN115671370 B CN 115671370B
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- China
- Prior art keywords
- microsphere
- drug
- water
- polyvinyl alcohol
- embolic
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- 239000004005 microsphere Substances 0.000 title claims abstract description 190
- 239000003814 drug Substances 0.000 title claims abstract description 161
- 230000003073 embolic effect Effects 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 118
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 62
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 62
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 25
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 19
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims abstract description 9
- 150000007942 carboxylates Chemical group 0.000 claims abstract description 8
- 125000000129 anionic group Chemical group 0.000 claims abstract description 6
- 125000000524 functional group Chemical group 0.000 claims abstract description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 4
- 208000005189 Embolism Diseases 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- -1 2, 2-dimethoxy ethyl Chemical group 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 32
- 150000001241 acetals Chemical group 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 14
- 229960004679 doxorubicin Drugs 0.000 claims description 14
- 238000013268 sustained release Methods 0.000 claims description 13
- 239000012730 sustained-release form Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- XFTALRAZSCGSKN-UHFFFAOYSA-M sodium;4-ethenylbenzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=C(C=C)C=C1 XFTALRAZSCGSKN-UHFFFAOYSA-M 0.000 claims description 10
- DZSVIVLGBJKQAP-UHFFFAOYSA-N 1-(2-methyl-5-propan-2-ylcyclohex-2-en-1-yl)propan-1-one Chemical compound CCC(=O)C1CC(C(C)C)CC=C1C DZSVIVLGBJKQAP-UHFFFAOYSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- 239000003999 initiator Substances 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 7
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 6
- HWDDJFFLFNQAFQ-UHFFFAOYSA-M potassium;4-ethenylbenzenesulfonate Chemical compound [K+].[O-]S(=O)(=O)C1=CC=C(C=C)C=C1 HWDDJFFLFNQAFQ-UHFFFAOYSA-M 0.000 claims description 6
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 5
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- 229920002301 cellulose acetate Polymers 0.000 claims description 5
- 229920006217 cellulose acetate butyrate Polymers 0.000 claims description 5
- 229960000908 idarubicin Drugs 0.000 claims description 5
- DXIHILNWDOYYCH-UHDJGPCESA-M sodium;(e)-3-phenylprop-2-enoate Chemical compound [Na+].[O-]C(=O)\C=C\C1=CC=CC=C1 DXIHILNWDOYYCH-UHDJGPCESA-M 0.000 claims description 5
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 4
- XBYUGDPGTDLUQF-UHFFFAOYSA-N C(C=C)(=O)O.S(=O)(=O)(O)CCC[K] Chemical compound C(C=C)(=O)O.S(=O)(=O)(O)CCC[K] XBYUGDPGTDLUQF-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 4
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 4
- 235000019438 castor oil Nutrition 0.000 claims description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- IWHVCHNCTHGORM-UHDJGPCESA-M potassium;(e)-3-phenylprop-2-enoate Chemical compound [K+].[O-]C(=O)\C=C\C1=CC=CC=C1 IWHVCHNCTHGORM-UHDJGPCESA-M 0.000 claims description 4
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 4
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 4
- 239000003549 soybean oil Substances 0.000 claims description 4
- 235000012424 soybean oil Nutrition 0.000 claims description 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 3
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 3
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 3
- 229960000975 daunorubicin Drugs 0.000 claims description 3
- 229960001904 epirubicin Drugs 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 229940057995 liquid paraffin Drugs 0.000 claims description 3
- VOPCZDADAYFWNS-UHFFFAOYSA-N n-(4,4-dimethoxybutyl)prop-2-enamide Chemical compound COC(OC)CCCNC(=O)C=C VOPCZDADAYFWNS-UHFFFAOYSA-N 0.000 claims description 3
- 229960001221 pirarubicin Drugs 0.000 claims description 3
- YZKHXQYZYCLCLE-UHFFFAOYSA-N S(=O)(=O)(O)CCC[K].C(C(=C)C)(=O)O Chemical compound S(=O)(=O)(O)CCC[K].C(C(=C)C)(=O)O YZKHXQYZYCLCLE-UHFFFAOYSA-N 0.000 claims 2
- 239000012567 medical material Substances 0.000 abstract description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 230000006872 improvement Effects 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 229920000642 polymer Polymers 0.000 description 21
- 150000001299 aldehydes Chemical class 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000008367 deionised water Substances 0.000 description 14
- 229910021641 deionized water Inorganic materials 0.000 description 14
- 238000011068 loading method Methods 0.000 description 14
- 239000002245 particle Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229920001661 Chitosan Polymers 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 229920002385 Sodium hyaluronate Polymers 0.000 description 7
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- 229940010747 sodium hyaluronate Drugs 0.000 description 7
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 6
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- SONHXMAHPHADTF-UHFFFAOYSA-M sodium;2-methylprop-2-enoate Chemical compound [Na+].CC(=C)C([O-])=O SONHXMAHPHADTF-UHFFFAOYSA-M 0.000 description 6
- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 description 5
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 5
- 229940047670 sodium acrylate Drugs 0.000 description 5
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- MAGFQRLKWCCTQJ-UHFFFAOYSA-N 4-ethenylbenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(C=C)C=C1 MAGFQRLKWCCTQJ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
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- 125000002947 alkylene group Chemical group 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
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- HEMMRECYDIMVFN-UHFFFAOYSA-L [K+].S(=O)(=O)([O-])CCCC=C(C(=O)[O-])C.[K+] Chemical compound [K+].S(=O)(=O)([O-])CCCC=C(C(=O)[O-])C.[K+] HEMMRECYDIMVFN-UHFFFAOYSA-L 0.000 description 3
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- NGFDECATWGNXPX-UHFFFAOYSA-L dipotassium 2-methylidene-5-sulfonatopentanoate Chemical compound [K+].[K+].[O-]C(=O)C(=C)CCCS([O-])(=O)=O NGFDECATWGNXPX-UHFFFAOYSA-L 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
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- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 2
- 150000000180 1,2-diols Chemical class 0.000 description 2
- 150000000185 1,3-diols Chemical group 0.000 description 2
- 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 2
- 229920000856 Amylose Polymers 0.000 description 2
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an embolic microsphere capable of slowly releasing a drug and a preparation method thereof, belonging to the technical field of medical materials. The microsphere takes polyvinyl alcohol as a main chain, the main chain is connected with water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures, and the water-soluble molecules are copolymerized into spheres through unsaturated bonds of the water-soluble molecules, water-soluble cross-linking agents containing anionic functional groups and unsaturated bonds and molecules of slow-release drugs containing carbon-carbon double bonds; the molecule of the slow-release medicine also has a carboxylate group or a sulfonate group and a benzene ring structure. The embolic microsphere capable of slowly releasing the medicine has good medicine carrying speed and medicine carrying quantity, has the capacity of slowly releasing the medicine, and has longer release time, simpler preparation method and mild reaction condition.
Description
The application is a divisional application with the application number of CN202111652538.7, the original application date is 2021, 12 months and 30 days, and the application is named as: an embolic microsphere capable of slowly releasing medicine and its preparation method are provided.
Technical Field
The invention relates to the technical field of medical materials, in particular to an embolic microsphere capable of slowly releasing a drug and a preparation method thereof.
Background
Trans-arterial chemoembolization (TACE) is a standard treatment widely used in patients with unresectable hepatocellular carcinoma, combining the therapeutic effects of peripheral arterial occlusion with local administration of chemotherapeutic agents, targeted and controlled delivery of chemotherapeutic agents. The selection of an appropriate embolic agent in combination with a chemotherapeutic agent, intravascularly delivered to specific sites in the body, embolizes, resulting in strong cytotoxic effects and ischemia. The drug-loaded embolism microsphere is the current latest embolic agent, can locally provide higher dose of chemotherapy drugs while embolizing tumor blood supply, and has the advantages of lower systemic toxicity and continuous local activity. The use of drug-loaded embolic microspheres significantly reduces the number of chemotherapeutic drugs that reach the systemic circulation, and significantly reduces adverse drug-related events, as compared to conventional iodized oil-based protocols.
The ideal drug-loaded embolism microsphere needs to have larger drug-loading capacity and faster drug-loading rate, and has smaller drug burst release and longer slow release time at the same time, so as to prolong the contact time of tumor drugs and tumors and realize better treatment effect. In article An In Vitro Evaluation of Four Types of Drug-Eluting Microspheres Loaded with Doxorubicin of Baere et al, the drug-loaded embolic microspheres DC Bead, LIFEPEARL, HEPASPHERES and Tanmem microspheres currently on the market have no slow release function when the time for eluting and releasing 75% of the total doxorubicin is 197, 139, 110 and 77min respectively. In vitro experiments show that even CALLISPHERES with the best slow release performance, the total amount of released doxorubicin exceeds 80% in 25 days, the long-term drug slow release capability is poor, and the sustained release time is short.
The traditional slow release technology is to disperse the drug in the polymer skeleton or wrap the drug inside the skeleton, so that the drug is slowly released along with the erosion of the skeleton. However, this contradicts the need for embolic microspheres that are "pre-existing products followed by rapid drug delivery". The current commercial embolic microspheres (e.g., DC Bead, CALLISPHERES, etc.) have ion exchange properties and can adsorb positively charged drugs, such as doxorubicin, which can actively absorb the chemotherapeutic drug in solution and release at a slower rate. However, the "burst" phenomenon exists during the initial release, the drug is released rapidly, the short-term (2 days) loss exceeds 30%, and the subsequent long-term release is not good.
CN106821993a describes a class of gel polymers crosslinked by disulfide-containing groups, wherein anionically charged groups are electrostatically associated with the drug for use in embolic therapy. The total amount of released doxorubicin is 8% at about 6 hours, the burst release phenomenon is still obvious, and the slow release effect is poor due to the lack of long-term experimental data.
CN111773428a discloses a medicine slow-release alginic acid embolism microsphere, which is prepared by compounding sodium alginate as raw material and positively charged chemotherapeutics in advance during preparation and then preparing medicine-carrying alginic acid embolism microsphere by using electrostatic spraying technology. The data show that the microsphere has slower drug release rate, but the preparation method needs to load the drug in advance, so that the storage condition of the finished microsphere is more severe so as to avoid the deterioration of the drug; in addition, the preparation method is complex and is not easy for mass production.
US5869103a provides a polylactic acid biodegradable microparticle, which is prepared by an emulsion/solvent extraction method, and the protein drug is dispersed in the microparticle after emulsification, and is slowly released along with the degradation of the microparticle, so that good linear release is shown. However, the drug needs to be added in the preparation process of the particles, high requirements are put on the stability of the drug and the particles, and the required drug cannot be flexibly selected by post-loading drug, so that the use of the particles is limited.
Disclosure of Invention
The invention aims to provide an embolic microsphere capable of slowly releasing a drug and a preparation method thereof, which have good drug carrying speed and drug carrying capacity, long release time, simple preparation method and mild reaction conditions.
The technical scheme of the invention is realized as follows:
The invention provides an embolic microsphere capable of slowly releasing a drug, which takes a polyhydroxy polymer as a main chain, and molecules capable of slowly releasing the drug are connected with the polyhydroxy polymer main chain through at least one carboxyl, acyl chloride, acyl bromide, aldehyde, hemiacetal or acetal structure which is contained in the microsphere and forms an acetal structure or an ester bond structure; the molecule of the slow-release medicine also contains a benzene ring structure. Carboxyl, acyl chloride, acyl bromide, aldehyde, hemiacetal or acetal structures on the molecules of the sustained release drug react with hydroxyl groups on the backbone of the microsphere to be linked together.
As a further improvement of the present invention, the sustained release drug molecule has a structure as shown in formula I:
wherein R is absent or 1-2 hydroxyl, amino or sulfonic acid groups, R 1 is- (CH 2)x-(O)y-(CH2)z -, wherein x=0, 1 or 2, y=0 or 1, z=0, 1 or 2;
r 2 is H, br, cl, Wherein R 3 is a benzene ring structure or an alkylene or alkene structure of 1 to 4 carbons, n=0 to 3, n 1 =0 to 3, preferably R 3 is an alkylene structure of 1 to 2 carbons, n=0, n 1 =0. The molecules with benzene ring structures are used as molecules capable of slowly releasing the medicine and are connected to the main chain of the microsphere, and the interaction between the microsphere and the medicine molecules is enhanced by utilizing pi-pi stacking effect of the benzene ring structures of the slow releasing molecules and the benzene ring structures of the medicine molecules, so that the microsphere has higher medicine carrying rate, higher medicine carrying quantity and capacity of slowly releasing the medicine.
As a further improvement of the present invention, the polyhydroxy polymer is a polymer or polysaccharide macromolecule comprising a 1, 2-diol or 1, 3-diol structure; preferably, the polymer is at least one of polyvinyl alcohol, chitosan, hyaluronate, alginate, amylose and modified cellulose.
As a further improvement of the present invention, the microspheres are copolymerized into spheres from a polyhydroxy polymer by linking a water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure and a crosslinking agent; the cross-linking agent is a water-soluble molecule containing an anionic functional group and an unsaturated bond.
As a further improvement of the present invention, the crosslinking agent is selected from at least one of carboxylic acid compounds having carboxylate groups and unsaturated bonds and derivatives thereof, sulfonic acid compounds having sulfonate groups and unsaturated bonds, or sulfonic acid salt compounds; wherein the carboxylic acid compound with carboxylate radicals and unsaturated bonds and derivatives thereof are at least one selected from acrylic acid, methacrylic acid, sodium acrylate and sodium methacrylate; the sulfonic acid compound or the sulfonate compound with sulfonate and unsaturated bond is selected from at least one of 2-acrylamide-2-methylpropanesulfonic acid, 2-acrylamide-2-methylpropanesulfonic acid sodium salt, 3-sulfopropyl acrylic acid potassium salt and 3-sulfopropyl methacrylic acid potassium salt.
As a further improvement of the present invention, the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure is at least one of N- (2, 2-dimethoxyethyl) -2-acrylamide, N-acrylamidoethyl acetal, 4-acrylamidobutyraldehyde methylal, N-acrylamidoacetal, 4-acrylamidophenylacetal.
As a further improvement of the present invention, the embolic microsphere is loaded with a drug that has at least one aromatic ring structure and is positively charged in an aqueous solution; preferably, the pharmaceutical composition is at least one of doxorubicin, epirubicin, pirarubicin, daunorubicin, idarubicin and idarubicin, and is Li Tikang.
The invention further provides a preparation method of the embolic microsphere capable of slowly releasing the drug, which comprises the following steps:
S1, adding a polyhydroxy polymer serving as a microsphere main chain into water for dissolution, adding a water-soluble molecule containing unsaturated bonds and aldehyde or acetal structures and inorganic acid serving as a first catalyst, adjusting the pH of a reaction system to 7-9 after the reaction is finished, and concentrating the solution to obtain a microsphere intermediate; water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures react with hydroxyl groups on the polyhydroxy polymer chains through aldehyde or acetal groups to form acetal structures, thereby functionalizing the polyhydroxy polymer chains; in this step, the length of the reaction time affects the yield, and it is usually possible to react at 10 to 35℃for 3 to 8 hours; the solution may be generally concentrated to a viscosity of 1500cps or more; preferably 1800cps;
S2, dissolving the microsphere intermediate prepared in the step S1, a cross-linking agent containing an anionic functional group and a water-soluble molecule with an unsaturated bond and an initiator in water, and adding a solvent and a surfactant to enable a reaction system to form a reversed-phase suspension polymerization system, so as to form microsphere particles with smooth surfaces and good spheres; then adding organic base as a second catalyst in inert gas atmosphere, filtering and washing after the reaction is finished to obtain microspheres taking polyhydroxy polymer as a main chain; in the step, the reaction temperature can be 55-65 ℃, the reaction time can be 2-6h, and transparent particles are formed in the visible solution after the reaction is finished;
S3, dispersing the microspheres with the polyhydroxy polymer as a main chain prepared in the step S2 in a solvent, adding molecules capable of slowly releasing the medicine for dissolution, adding acid as a catalyst to form a solution, reacting, removing the solvent, and cleaning to obtain embolic microspheres capable of slowly releasing the medicine; the molecule of the slow-release medicine contains at least one carboxyl, acyl chloride, acyl bromide, aldehyde, hemiacetal or acetal structure and one benzene ring structure, and is connected with hydroxyl on the main chain of the polyhydroxy polymer through ester bond or acetal structure.
As a further improvement of the present invention, the sustained release drug molecule has a structure as shown in formula I:
wherein R is absent or 1-2 hydroxyl, amino or sulfonic acid groups, R 1 is- (CH 2)x-(O)y-(CH2)z -, wherein x=0, 1 or 2, y=0 or 1, z=0, 1 or 2;
r 2 is H, br, cl, Wherein R 3 is a benzene ring structure or an alkylene or alkene structure of 1 to 4 carbons, n=0 to 3, n 1 =0 to 3, preferably R 3 is an alkylene structure of 1 to 2 carbons, n=0, n 1 =0.
As a further improvement of the present invention, the mass ratio of the polyhydroxy polymer, the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure, and the first catalyst in step S1 is 1: (0.01-0.5): (0.05-5).
As a further improvement of the present invention, the polyhydroxy polymer is a polymer or polysaccharide macromolecule comprising a 1, 2-diol or 1, 3-diol structure; preferably, the polymer is at least one of polyvinyl alcohol, chitosan, hyaluronate, alginate, amylose and modified cellulose;
as a further improvement of the present invention, the initiator in step S2 is at least one selected from the group consisting of potassium persulfate, ammonium persulfate, and sodium persulfate.
As a further improvement of the present invention, the crosslinking agent in step S2 is selected from at least one of carboxylic acid compounds having carboxylate groups and unsaturated bonds and derivatives thereof, sulfonic acid compounds having sulfonate groups and unsaturated bonds, or sulfonate compounds; wherein the carboxylic acid compound with carboxylate radicals and unsaturated bonds and derivatives thereof are at least one selected from acrylic acid, methacrylic acid, sodium acrylate and sodium methacrylate; the sulfonic acid compound or the sulfonate compound with sulfonate and unsaturated bond is selected from at least one of 2-acrylamide-2-methylpropanesulfonic acid, 2-acrylamide-2-methylpropanesulfonic acid sodium salt, 3-sulfopropyl acrylic acid potassium salt and 3-sulfopropyl methacrylic acid potassium salt.
As a further improvement of the present invention, the mass ratio of the microsphere intermediate, the crosslinking agent, the initiator, the water, the solvent, the surfactant and the organic base in the step S2 is 1: (0.001-0.2): (0.0001-0.05): (0.1-3): (4-50): (0.001-0.1): (0.0001-0.05).
As a further improvement of the present invention, the acid in step S3 is an organic acid or an inorganic acid, preferably at least one of concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid, methanesulfonic acid, glacial acetic acid, citric acid, benzoic acid, perchloric acid.
As a further improvement of the present invention, the solvent in step S3 is a polar solvent, preferably at least one of dimethyl sulfoxide, water, acetone, acetonitrile, N-methylpyrrolidone.
As a further improvement of the invention, the mass fraction of the microspheres in the solution in the step S3 is 1% -30%; the mass concentration of the molecules of the slow-release medicine in the solution is 0.01-2mol/L; the concentration of the acid in the solution is 0.05-10mol/L.
As a further improvement of the invention, the temperature of the reaction in the step S3 is between room temperature and 120 ℃ and the reaction time is between 15min and 48h.
As a further improvement of the present invention, the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure is at least one of N- (2, 2-dimethoxyethyl) -2-acrylamide, N-acrylamidoethyl acetal, 4-acrylamidobutyraldehyde methylal, N-acrylamidoacetal, 4-acrylamidophenylacetal; the first catalyst is concentrated hydrochloric acid or concentrated sulfuric acid; the solvent in the S2 is at least one of butyl acetate, ethyl acetate, liquid paraffin, castor oil, soybean oil, n-heptane or cyclohexane; the surfactant is at least one of cellulose acetate butyrate, cellulose acetate, span 20, span 80, tween 20 and tween 80; the second catalyst is at least one of tetramethyl ethylenediamine, triethylamine and N, N-dimethylaniline.
The invention further protects an embolic microsphere capable of slowly releasing drugs, which takes polyvinyl alcohol as a main chain, the main chain is connected with water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures, and the water-soluble molecules are copolymerized into spheres through the unsaturated bonds of the water-soluble molecules, water-soluble cross-linking agents containing anionic functional groups and unsaturated bonds and molecules containing carbon-carbon double bonds and capable of slowly releasing drugs; the molecule of the slow-release medicine also has a carboxylate group or a sulfonate group and a benzene ring structure. The water-soluble molecule containing unsaturated bond and aldehyde or acetal structure is connected with hydroxyl of main chain through aldehyde or acetal group, so that the main chain is connected with double bond, and the water-soluble molecule is copolymerized with double bond of crosslinking agent and molecules capable of slowly releasing medicine, and the main chain is connected to form ball, and at the same time the molecules capable of slowly releasing medicine are connected to microsphere.
As a further improvement of the present invention, the molecule of the slow-release drug is at least one selected from sodium p-styrenesulfonate, potassium p-styrenesulfonate, sodium cinnamate, and potassium cinnamate.
As a further improvement of the present invention, the crosslinking agent is selected from at least one of carboxylic acid compounds having carboxylate groups and unsaturated bonds and derivatives thereof, sulfonic acid compounds having sulfonate groups and unsaturated bonds, or sulfonic acid salt compounds; wherein the carboxylic acid compound with carboxylate radicals and unsaturated bonds and derivatives thereof are at least one selected from acrylic acid, methacrylic acid, sodium acrylate and sodium methacrylate; the sulfonic acid compound or the sulfonate compound with sulfonate and unsaturated bond is selected from at least one of 2-acrylamide-2-methylpropanesulfonic acid, 2-acrylamide-2-methylpropanesulfonic acid sodium salt, 3-sulfopropyl acrylic acid potassium salt and 3-sulfopropyl methacrylic acid potassium salt.
As a further improvement of the present invention, the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure is at least one of N- (2, 2-dimethoxyethyl) -2-acrylamide, N-acrylamidoethyl acetal, 4-acrylamidobutyraldehyde methylal, N-acrylamidoacetal, 4-acrylamidophenylacetal.
As a further improvement of the present invention, the embolic microsphere is loaded with a drug that has at least one aromatic ring structure and is positively charged in an aqueous solution; preferably, the pharmaceutical composition is at least one of doxorubicin, epirubicin, pirarubicin, daunorubicin, idarubicin and idarubicin, and is Li Tikang.
As a further improvement of the present invention, the weight average molecular weight of the polyvinyl alcohol is 30000 to 80000.
The invention further provides a preparation method of the embolic microsphere capable of slowly releasing the drug according to the claims, which comprises the following steps:
S1, preparing a polyvinyl alcohol embolism microsphere intermediate: adding polyvinyl alcohol into water for dissolution, adding water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures and inorganic acid as a first catalyst, adjusting the pH of a reaction system to 7-9 after the reaction is finished, and concentrating the solution to obtain a polyvinyl alcohol embolism microsphere intermediate; in this step, the length of the reaction time affects the yield, and it is usually possible to react at 10 to 35℃for 3 to 8 hours; typically the solution is concentrated to a viscosity of 1500cps or more, more preferably 1800cps or more;
S2, preparing embolic microspheres capable of slowly releasing the drugs: adding the intermediate of the polyvinyl alcohol embolism microsphere prepared in the step S1, molecules of a slow-release drug, a cross-linking agent and an initiator into water for dissolution, and then adding a solvent and a surfactant to enable a reaction system to form a water-in-oil reverse phase suspension polymerization system, so as to form microsphere particles with smooth surfaces and good spheres; then adding organic base as a second catalyst in inert gas atmosphere, and washing after the reaction is finished to obtain the embolic microsphere capable of slowly releasing the drug; in this step, the reaction temperature may be 55 to 65℃and the reaction time may be 2 to 6 hours;
The molecule of the slow-release medicine contains a carbon-carbon double bond, a carboxylate group or a sulfonate group and a benzene ring structure;
the cross-linking agent is a water-soluble molecule containing an anionic functional group and an unsaturated bond.
As a further improvement of the present invention, the molecule of the slow-release drug is at least one selected from sodium p-styrenesulfonate, potassium p-styrenesulfonate, sodium cinnamate, and potassium cinnamate.
As a further improvement of the present invention, the weight average molecular weight of the polyvinyl alcohol in step S1 is 30000-80000.
As a further improvement of the present invention, the mass ratio of the polyvinyl alcohol, the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure, and the first catalyst in step S1 is 1: (0.01-0.5): (0.05-5).
As a further improvement of the present invention, the initiator in step S2 is at least one selected from the group consisting of potassium persulfate, ammonium persulfate, and sodium persulfate.
As a further improvement of the invention, the mass ratio of the intermediate of the polyvinyl alcohol embolic microsphere, the molecules of the slow-release drug, the cross-linking agent, the initiator, the water, the solvent, the surfactant and the second catalyst in the step S2 is 1: (0.01-0.5): (0.001-0.2): (0.0001-0.05): (0.1-3): (4-50): (0.001-0.1): (0.0001-0.05)
As a further improvement of the present invention, the crosslinking agent in step S2 is selected from at least one of carboxylic acid compounds having carboxylate groups and unsaturated bonds and derivatives thereof, sulfonic acid compounds having sulfonate groups and unsaturated bonds, or sulfonate compounds; wherein, the carboxylic acid compound with carboxylate radicals and unsaturated bonds and derivatives thereof are preferably at least one of acrylic acid, methacrylic acid, sodium acrylate and sodium methacrylate; the sulfonic acid compound or the sulfonate compound having a sulfonate group and an unsaturated bond is preferably at least one of 2-acrylamide-2-methylpropanesulfonic acid, sodium 2-acrylamide-2-methylpropanesulfonate, potassium 3-sulfopropyl acrylate, and potassium 3-sulfopropyl methacrylate.
As a further improvement of the present invention, the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure is at least one of N- (2, 2-dimethoxyethyl) -2-acrylamide, N-acrylamidoethyl acetal, 4-acrylamidobutyraldehyde methylal, N-acrylamidoacetal, 4-acrylamidophenylacetal; the first catalyst is concentrated hydrochloric acid or concentrated sulfuric acid; at least one of butyl acetate, ethyl acetate, liquid paraffin, castor oil, soybean oil, n-heptane or cyclohexane in the S2; the surfactant is at least one of cellulose acetate butyrate, cellulose acetate, span 20, span 80, tween 20 and tween 80; the second catalyst is at least one of tetramethyl ethylenediamine, triethylamine and N, N-dimethylaniline.
The beneficial effects are that: the embolic microsphere with the slow release function provided by the invention has the advantages of higher drug carrying rate, higher drug carrying capacity and drug slow release capacity. The embolic microsphere is loaded with the medicine which has at least one aromatic ring structure and is positively charged in aqueous solution, such as doxorubicin and the like, has good medicine carrying speed and medicine carrying capacity, has excellent capacity of slowly releasing the medicine, and has longer release time and no burst release phenomenon compared with the existing commercial embolic microsphere.
The principle of realizing slow release of the drug molecules is that molecules with benzene ring structures are used as slow release molecules and are connected to a microsphere main chain, and interaction between the microsphere and the drug molecules is enhanced by utilizing pi-pi stacking effect of the benzene ring structures of the slow release molecules and the benzene ring structures of the drug molecules, so that the microsphere has higher drug loading rate, higher drug loading capacity and drug slow release capacity. In addition, the existence of benzene rings in the microsphere structure also increases the steric effect inside the microsphere, and reduces the diffusion rate of drug molecules inside the microsphere, thereby reducing the release rate of the microsphere drug.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that other drawings can be obtained according to these drawings without inventive faculty for a person skilled in the art.
FIG. 1 is a microscopic image of a drug-sustained release polyvinyl alcohol drug-loaded embolic microsphere prepared in example 1;
FIG. 2 is an infrared spectrum of the drug-loaded plug microsphere of polyvinyl alcohol, which can release drugs slowly, prepared in example 1;
FIG. 3 is a microscopic image of the drug-eluting polyvinyl alcohol drug-loaded embolic microspheres prepared in example 5;
FIG. 4 is an infrared spectrum of the drug-loaded plug microsphere of polyvinyl alcohol, which can release drugs slowly, prepared in example 5;
FIG. 5 is a microscopic image of the drug-eluting plug microsphere of polyvinyl alcohol loaded with doxorubicin prepared in example 1;
FIG. 6 is a microscopic photograph of the drug-releasing plug microsphere of polyvinyl alcohol loaded with doxorubicin prepared in example 5.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The embodiment provides a method for preparing a polyvinyl alcohol embolism microsphere capable of slowly releasing a drug by using N- (2, 2-dimethoxy ethyl) -benzamide, which specifically comprises the following steps:
S1, preparing polyvinyl alcohol embolism microspheres:
S11, adding 60g of polyvinyl alcohol with a weight average molecular weight of 67000 into 400mL of purified water, and completely dissolving at 90 ℃. Then, 0.9g N- (2, 2-dimethoxyethyl) -2-acrylamide and 35mL of 37.5wt% concentrated hydrochloric acid were added and reacted at 30℃for 6 hours. After the reaction was completed, the pH of the reaction system was adjusted to 7.5 with a 2mol/L sodium hydroxide solution. Finally, the solution is concentrated to a viscosity equal to 1800cps to obtain microsphere intermediates.
S12, 15g of the microsphere intermediate, 1.7g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt and 0.45g of potassium persulfate are completely dissolved in 5mL of deionized water. 104mL of butyl acetate and 0.25g of cellulose acetate butyrate were added, and finally 0.2mL of tetramethyl ethylenediamine was added under nitrogen atmosphere, and reacted at 55℃for 6 hours. And after the reaction is finished, filtering, and washing with ethyl acetate, acetone and deionized water to obtain the polyvinyl alcohol embolism microsphere.
S2, preparing polyvinyl alcohol embolism microspheres capable of slowly releasing the medicine:
In a 2L reaction flask, 500mL of dimethyl sulfoxide was added, 20g of the polyvinyl alcohol microsphere prepared in the above step was added, and 10.6g N- (2, 2-dimethoxyethyl) -benzamide was added and dissolved by stirring. Then 30mL of 37.5wt% concentrated hydrochloric acid was slowly added. After the completion of the dropwise addition, the temperature was raised to 80℃and the reaction was carried out for 2 hours. After the reaction, white particles are precipitated at the bottom of the reaction flask, and the upper layer reaction solvent is removed. And adding 500mL of dimethyl sulfoxide, stirring and cleaning for 10min, removing the solvent, adding 500mL of deionized water, stirring and cleaning for 10min, and repeating the process twice to obtain 18g of polyvinyl alcohol embolic microspheres capable of slowly releasing the drug. Fig. 1 is a microscopic image of the resulting microsphere, which is observed to change from colorless transparent to translucent light white, while still maintaining good sphericity and dispersibility, as compared to the pre-reaction microsphere. FIG. 2 is an infrared spectrum of the resulting microsphere. Wherein 1650cm -1 and 1519cm -1 are characteristic peaks of amide bonds; 865cm -1 and 681cm -1 are characteristic peaks of benzene rings.
Example 2
The embodiment provides a method for preparing chitosan embolism microsphere capable of slowly releasing medicine by benzoyl chloride, which comprises the following steps:
S1, preparing chitosan embolism microspheres:
S11, 15g of chitosan with the weight average molecular weight of about 100000 is taken and added into 50g of water, the water is heated to 95 ℃, the water is stirred for 3 hours to dissolve completely, 0.55g N-acrylamide diethyl acetal and 2mL of concentrated sulfuric acid are added, and the reaction is carried out for 5 hours at 25 ℃. After the completion of the reaction, the pH of the reaction system was adjusted to 7.2 with a 0.5mol/L sodium hydroxide solution. Finally, the solution is concentrated to a viscosity equal to 1800cps to obtain microsphere intermediates.
S12, 1.6g of 3-sulfopropyl potassium acrylate and 0.86g of potassium persulfate are weighed and dissolved completely in 10mL of deionized water, and 30g of the microsphere intermediate is added. 300mL of ethyl acetate and 3.55g of cellulose acetate were further added, and 1mL of triethylamine was added under a nitrogen atmosphere to react at 60℃for 4 hours. And after the reaction is finished, filtering, and washing with ethyl acetate, acetone and deionized water to obtain the chitosan embolism microsphere.
S2, preparing chitosan embolism microspheres capable of slowly releasing medicines:
10g of the chitosan embolism microsphere prepared in the above steps is taken and added into 50mL of acetone at room temperature, 5g of benzoyl chloride is added, 3g of glacial acetic acid is added dropwise, and the temperature is kept at 25 ℃ and stirring is carried out for 24 hours. At the end of the reaction, white particles precipitated to the bottom of the reaction flask. The particles are respectively washed by clean acetone, ethanol and deionized water, and 8g of chitosan embolism microsphere capable of slowly releasing the medicine is obtained.
Example 3
The embodiment provides a method for preparing sodium hyaluronate embolic microspheres capable of slowly releasing medicines by using benzaldehyde, which specifically comprises the following steps:
s1, preparing sodium hyaluronate embolism microspheres:
S11, 20g of sodium hyaluronate with the weight average molecular weight of 140000 is taken and added into 50g of water, the mixture is heated to 80 ℃, stirred for 2 hours to dissolve completely, and 0.3g N-acrylamide acetaldehyde and 8mL of 37.5wt% concentrated hydrochloric acid are added for reaction for 3 hours at 30 ℃. After the completion of the reaction, the pH of the reaction system was adjusted to 7.3 with a 0.5mol/L sodium hydroxide solution. Finally, the solution is concentrated to a viscosity equal to 2000cps to obtain microsphere intermediates.
S12, 20g of the microsphere intermediate, 1.5g of sodium acrylate and 0.2g of sodium persulfate are completely dissolved in 20mL of deionized water. 180mL of soybean oil and 1.5g of span 20 were added, and finally 0.35mL of N, N-dimethylaniline was added under nitrogen atmosphere to react at 65℃for 6 hours. And after the reaction is finished, filtering, and washing with ethyl acetate, acetone and deionized water to obtain the sodium hyaluronate embolic microspheres.
S2, preparing sodium hyaluronate embolism microsphere capable of slowly releasing medicine:
Adding 1.5g of sodium hyaluronate embolism microsphere prepared in the above step into 5mL of N-methyl pyrrolidone solution to obtain microsphere solution; 10.9g of benzaldehyde is dissolved in 45mL of dimethyl sulfoxide, added to the microsphere solution, 9.6g of methanesulfonic acid is then added, heated to 90 ℃ and stirred for 15min. At the end of the reaction, the particles were seen to precipitate to the bottom of the reaction flask. The microparticles are respectively washed by dimethyl sulfoxide, ethanol and deionized water to obtain 1g of sodium hyaluronate embolic microspheres capable of slowly releasing the drug.
Example 4
The embodiment provides a method for preparing carboxymethyl cellulose embolic microspheres capable of slowly releasing medicines by using N- (2, 2-dimethoxy ethyl) -2-hydroxybenzoamide, which comprises the following steps:
s1, preparing carboxymethyl cellulose embolism microsphere:
s11, 15g of sodium carboxymethylcellulose with the weight-average molecular weight of about 90000 is taken and added into 50g of water, the mixture is heated to 90 ℃, stirred for 3 hours to dissolve completely, and then 0.85g of 4-acrylamidophenylacetaldehyde and 6.3mL of 37.5wt% concentrated hydrochloric acid are added for reaction for 5 hours at 25 ℃. After the completion of the reaction, the pH of the reaction system was adjusted to 8.0 with a 2mol/L sodium hydroxide solution. Finally, the solution was concentrated to a viscosity equal to 2200cps to give a microsphere intermediate.
S12, weighing 2.4g of sodium methacrylate and 1.5g of ammonium persulfate, dissolving the sodium methacrylate and the ammonium persulfate in 10mL of deionized water completely, and adding 30g of the microsphere intermediate. Then, 332mL of cyclohexane and 8g of Tween 20 were added, 1.7mL of ethylenediamine was added under an argon atmosphere, and the mixture was reacted at 60℃for 4 hours. After the reaction is finished, filtering, washing with ethyl acetate and acetone, and obtaining the carboxymethyl cellulose embolism microsphere.
S2, preparing carboxymethyl cellulose embolism microsphere capable of slowly releasing medicine:
10g of carboxymethyl cellulose embolic microspheres prepared in the above steps are dispersed in 400mL of acetonitrile, 9.5g N- (2, 2-dimethoxy ethyl) -2-hydroxybenzoamide is dissolved in 100mL of acetonitrile, 10mL of 98wt% concentrated sulfuric acid is added dropwise, and the temperature is kept at 60 ℃ and stirred for 6 hours. At the end of the reaction, particles are precipitated at the bottom of the reaction flask. And (3) adding 500mL of acetonitrile after removing the upper reaction solvent, stirring and cleaning for 10min, removing acetonitrile, adding 500mL of deionized water, stirring and cleaning for 10min, and repeating the process twice to obtain 7g of carboxymethyl cellulose embolism microsphere capable of slowly releasing the medicine.
Example 5
The embodiment provides a preparation method of a polyvinyl alcohol embolism microsphere capable of slowly releasing a drug, which specifically comprises the following steps:
s1, preparing a polyvinyl alcohol embolism microsphere intermediate:
Into the reaction flask, 100g of purified water and 10g of polyvinyl alcohol having a weight average molecular weight of 67000 were charged, and the mixture was heated to 90℃to completely dissolve the polyvinyl alcohol. 1.1g N- (2, 2-dimethoxyethyl) -2-acrylamide and 20mL 37wt% concentrated hydrochloric acid were added and reacted at 25℃for 5 hours, after the completion of the reaction, the pH of the reaction system was adjusted to 7.2 with 2mol/L sodium hydroxide solution. And finally, concentrating the solution until the viscosity is 2000cps to obtain the intermediate of the polyvinyl alcohol plug-carrying microsphere.
S2, preparing polyvinyl alcohol embolism microspheres capable of slowly releasing the medicine:
10g of the intermediate of the polyvinyl alcohol embolism microsphere prepared in the above step, 3g of sodium p-styrenesulfonate, 0.5g of sodium 2-acrylamide-2-methylpropanesulfonate, 0.3g of potassium persulfate and 5mL of water are added into a reaction bottle to be completely dissolved. 70mL of butyl acetate and 0.7g of cellulose acetate butyrate were added, and after nitrogen was introduced, 0.5mL of tetramethyl ethylenediamine was added and reacted at 55℃for 6 hours. Finally, washing with ethyl acetate, acetone and deionized water in sequence to obtain 40g of polyvinyl alcohol embolism microsphere capable of slowly releasing the medicine.
Fig. 3 is a microscopic image of the slow-release drug-releasing polyvinyl alcohol embolic microsphere prepared in example 5, and it can be seen from the figure that the polyvinyl alcohol embolic microsphere has round particles, smooth surface and good dispersibility. FIG. 4 is an infrared spectrum of the polyvinyl alcohol embolic microsphere of the sustained release drug prepared in example 5. Wherein 871cm -1、808cm-1、777cm-1、709cm-1 is the characteristic peak of benzene ring, which proves that sodium p-styrenesulfonate is copolymerized in the polymer network of the microsphere.
Example 6
The embodiment provides a preparation method of a polyvinyl alcohol embolism microsphere capable of slowly releasing a drug, which specifically comprises the following steps:
s1, preparing a polyvinyl alcohol plug-carrying microsphere intermediate:
50g of purified water and 6g of polyvinyl alcohol having a weight average molecular weight of 80000 were charged into a reaction flask, and the mixture was heated to 97℃to completely dissolve the polyvinyl alcohol. 0.15g of 4-acrylamidobutyraldehyde dimethyl acetal and 3mL of 37wt% concentrated hydrochloric acid were added and reacted at 10℃for 8 hours, after the completion of the reaction, the pH of the reaction system was adjusted to 8 with 2mol/L sodium hydroxide solution. And finally, concentrating the solution until the viscosity is 2200cps to obtain the intermediate of the polyvinyl alcohol embolism microsphere.
S2, preparing polyvinyl alcohol embolism microspheres capable of slowly releasing the medicine:
10g of the polyvinyl alcohol embolic microsphere intermediate prepared in the above step, 1g of potassium p-styrene sulfonate, 0.08g of 3-sulfopropyl potassium acrylate, 0.006g of ammonium persulfate and 4mL of water are added into a reaction flask to be completely dissolved. 25mL of butyl acetate and 0.01g of cellulose acetate were added, and after introducing nitrogen, 0.02mL of triethylamine was added and reacted at 60℃for 5 hours. Finally, washing with ethyl acetate, acetone and deionized water in sequence to obtain 35g of polyvinyl alcohol embolism microsphere capable of slowly releasing the medicine.
Example 7
The embodiment provides a preparation method of a polyvinyl alcohol embolism microsphere capable of slowly releasing a drug, which specifically comprises the following steps:
s1, preparing a polyvinyl alcohol embolism microsphere intermediate:
1000g of purified water and 300g of polyvinyl alcohol having a weight average molecular weight of 32000 were added to the reaction flask, and the mixture was heated to 85℃to completely dissolve the polyvinyl alcohol. 110g N-acrylamidoaldehyde and 50mL 98wt% concentrated sulfuric acid were added and reacted at 20℃for 5 hours, after the reaction was completed, the pH of the reaction system was adjusted to 9 with 0.5mol/L sodium hydroxide solution. And finally, concentrating the solution until the viscosity is 2500cps to obtain the intermediate of the polyvinyl alcohol embolism microsphere.
S2, preparing polyvinyl alcohol embolism microspheres capable of slowly releasing the medicine:
Into the reaction flask, 100g of a polyvinyl alcohol embolic microsphere intermediate, 25g of sodium cinnamate, 19g of 2-acrylamide-2-methylpropanesulfonic acid, 1g of potassium persulfate and 25mL of water were added and dissolved completely. 900mL of castor oil and 0.15g of Tween 80 were added, and after nitrogen introduction, 1.4mL of ethylenediamine was added and reacted at 65℃for 3 hours. Finally, washing sequentially by ethyl acetate, acetone and deionized water to obtain 450g of polyvinyl alcohol embolism microsphere capable of slowly releasing the medicine.
Comparative example 1
The difference compared to example 1 is that step S2 is not passed.
Comparative example 2
The difference compared to example 2 is that the benzoyl chloride in step S2 is replaced with acetyl chloride.
Comparative example 3
The difference compared to example 3 is that step S2 is not passed.
Comparative example 4
In comparison with example 5, the difference is that sodium p-styrenesulfonate is not added in step S2.
Comparative example 5 preparation of sodium Poly (p-styrenesulfonate) microspheres
In a four-necked flask, 1.7g of ethylcellulose was added to 40mL of toluene, and the mixture was heated at 60℃for 2 hours to dissolve, and the mixture was purged with nitrogen. 3.8g of sodium p-styrenesulfonate and 0.21g of N, N' -methylenebisacrylamide are dissolved in 15mL of distilled water under stirring, and added into the four-necked flask; dropwise adding 0.0475g of ammonium persulfate dissolved in 5mL of distilled water into the solution for about 10min; stirring at 250rpm and 65 ℃, reacting for 4 hours at constant temperature, filtering, repeatedly washing with ethanol and distilled water, and drying to constant weight to obtain 8g of poly (sodium p-styrenesulfonate) microspheres.
Comparative example 6 preparation of embolic microspheres for sustained release of drugs Using styrene
The difference compared to example 6 is that the potassium p-styrenesulfonate in step S2 is replaced with styrene.
Test example 1 Adriamycin drug loading experiment
Test object: embolic microspheres of the sustained release drugs prepared in examples 1 to 7 and microspheres prepared in comparative examples 1 to 6.
The testing method comprises the following steps: the surface of the microsphere was blotted with filter paper, 1g of microsphere was weighed into a penicillin bottle, 4mL of 20mg/mL doxorubicin hydrochloride aqueous solution was added, the penicillin bottle was sealed and placed on a circumferential shaker and oscillated at 180rpm, 10 μl of sample was blotted at preset time points and diluted to 2mL, respectively.
The concentration of doxorubicin hydrochloride solution was measured at 480nm using an ultraviolet spectrophotometer, and the adsorption amount and drug loading rate of the microsphere drug were calculated, and the results are shown in tables 1 and 2.
TABLE 1
TABLE 2
As can be seen from tables 1 and 2, the drug-loaded embolism microsphere capable of slowly releasing the drug prepared by the invention has higher load of doxorubicin and is superior to a comparative sample without drug-releasing molecules in a microsphere polymer network. The interaction between the microsphere and the drug molecule is enhanced due to pi-pi stacking effect of the benzene ring structure of the slow release molecule and the benzene ring structure of the drug molecule in the microsphere structure, so that the drug loading rate and the drug loading quantity of the microsphere are improved. The sodium poly (p-styrenesulfonate) microsphere prepared in comparative example 5 has very high rigidity and poor hydrophilicity of the molecular chain because the molecular chain is fully provided with benzene rings, so that the microsphere is difficult to absorb the drug solution; at the same time, the steric hindrance effect also prevents the drug molecules from entering the interior of the microsphere. The drug loading and drug loading rate of comparative example 6 were significantly reduced due to poor hydrophilicity of styrene, and low reaction with other monomers during the preparation of microspheres, which resulted in uneven polymerization of microspheres and reduced drug loading capacity of microspheres.
Fig. 5 and 6 are microscope pictures of the polyvinyl alcohol embolic microspheres with the sustained release drugs prepared in examples 1 and 5, respectively, after the drug-loaded microspheres still have good sphericity and dispersibility, the microspheres turn red, and the microspheres are shown to have been loaded with a large amount of doxorubicin.
Test example 2 Adriamycin in vitro Release test
Test object: the test example 1 was taken and subjected to the experiment.
The testing method comprises the following steps: after the surface moisture of the microspheres after drug loading is absorbed by filter paper, 0.25g of microspheres is precisely weighed into a 100mL brown penicillin bottle, 100mL phosphate buffer salt solution is added, the penicillin bottle is covered tightly, and the microspheres are placed into a constant temperature water bath shaking table preheated to 37 ℃ and are oscillated at the speed of 100rpm and start timing. 2mL of the sample solution was aspirated from the flask at a predetermined time point and filled. The experiment was started with intensive sampling, the sampling times were gradually reduced after three days, but the PBS medium was replaced at least once daily, sampling test was performed before medium replacement, and sampling time was recorded.
The concentration of doxorubicin in the solution was measured at 480nm using an ultraviolet spectrophotometer, and the cumulative release rate of the drug was calculated, and the results are shown in tables 3 and 4.
TABLE 3 Table 3
TABLE 4 Table 4
As can be seen from tables 3 and 4, the embolic microspheres of the sustained release drugs prepared in examples 1 to 7 of the present invention had a release rate of at least 43.33% up to 49.99% and a release rate of at least 81.51% up to 99.68% in a phosphate buffered saline solution, shaking at 37℃and 100rpm, and changing the medium every day, compared to the samples in which the molecules for sustained release drugs were not bound in the microsphere polymer network. In addition, the product of the invention has light burst release effect and stable release speed, and releases about 1.5% of the product every day from the third day. The benzene ring on the slow release molecule in the microsphere structure has stronger interaction with the drug molecule, thereby realizing the slow release of the drug. In addition, the existence of benzene rings in the microsphere structure also increases the steric effect inside the microsphere, reduces the diffusion rate of drug molecules inside the microsphere, and also leads to the slow release rate of the microsphere drug. The sodium poly (p-styrenesulfonate) microsphere prepared in comparative example 5 has very high rigidity and poor hydrophilicity of the molecular chain because the molecular chain is fully provided with benzene rings, so that the microsphere is difficult to absorb the drug solution; meanwhile, the steric hindrance effect also prevents the drug molecules from entering the microsphere, so that the drug molecules are only adsorbed on the surface of the poly (sodium p-styrenesulfonate) microsphere, and the burst release phenomenon is obvious. The microsphere prepared in comparative example 6 did not show a significant slow release effect, because the drug loading of the microsphere prepared in comparative example 6 was low and the distribution of benzene rings in the microsphere was less and non-uniform, resulting in faster diffusion release of drug molecules.
Test example 3 catheter passability test of embolic microspheres with sustained Release of drug
Test object:
Embolic microspheres prepared in examples 1-7 and comparative examples 1-5.
The testing method comprises the following steps: microspheres with a particle size range of 100 to 300 μm among the embolic microspheres prepared in examples 1 to 7 and comparative examples 1 to 5 were dispersed in physiological saline. The microsphere dispersion was then aspirated into a 10mL syringe, air and supernatant were removed, and only the microspheres were retained. And then sucking 10mL of medical contrast agent, uniformly mixing the microspheres in the 10mL of syringe with the contrast agent, transferring the mixed solution of the microspheres and the contrast agent in the 10mL of syringe into the 3mL of syringe by utilizing a three-way joint, and then connecting the 3mL of syringe with the microcatheter with the corresponding inner diameter after being washed by the normal saline. The injection needle tube is rocked to enable the microspheres to be slowly and uniformly injected back into the original bottle through the catheter, and the injection speed is 1mL/min. Too fast an injection will cause the liquid to first pass through the catheter, leaving behind microspheres. Finally, whether the microsphere blocks the catheter or not and the difficulty of passing through the catheter are observed.
The results are shown in tables 5 and 6.
TABLE 5
TABLE 6
The result shows that the drug-loaded embolic microsphere capable of slowly releasing the drug prepared by the technology has good catheter trafficability and can meet the requirements of clinical delivery of the microsphere through a catheter. The sodium poly (p-styrenesulfonate) microsphere prepared in comparative example 5 has poor elasticity due to high rigidity of the molecular chain because the molecular chain is fully distributed with benzene rings, and cannot be transported through a catheter.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (10)
1. An embolic microsphere for supporting a drug which has at least one aromatic ring structure and is positively charged in an aqueous solution, wherein the microsphere comprises a main chain of polyvinyl alcohol, the main chain is connected with a water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure, and the microsphere is copolymerized with a water-soluble crosslinking agent containing an anionic functional group and an unsaturated bond and a molecule of the drug which has a carbon-carbon double bond and is slowly released; the molecule of the slow-release medicine also has a carboxylate group or a sulfonate group and a benzene ring structure; the water-soluble molecule is at least one of N- (2, 2-dimethoxy ethyl) -2-acrylamide, 4-acrylamido butyraldehyde dimethyl acetal and N-acrylamido acetaldehyde; the cross-linking agent is at least one selected from 2-acrylamide-2-methylpropanesulfonic acid, 2-acrylamide-2-methylpropanesulfonic acid sodium, 3-sulfopropyl potassium acrylate and 3-sulfopropyl potassium methacrylate; the molecule of the slow-release medicine is at least one selected from sodium p-styrenesulfonate, potassium p-styrenesulfonate, sodium cinnamate and potassium cinnamate.
2. The slowly-releasing drug embolic microsphere according to claim 1, wherein the drug positively charged in aqueous solution is at least one of doxorubicin, epirubicin, pirarubicin, daunorubicin, idarubicin, and i Li Tikang.
3. The drug-eluting embolic microsphere according to claim 1, wherein the weight average molecular weight of the polyvinyl alcohol is 30000-80000.
4. A method of preparing embolic microspheres with sustained release of a drug according to any one of claims 1-3, comprising the steps of:
S1, preparing a polyvinyl alcohol embolism microsphere intermediate: adding polyvinyl alcohol into water for dissolution, adding water-soluble molecules containing unsaturated bonds and aldehyde or acetal structures and inorganic acid as a first catalyst, adjusting the pH of a reaction system to 7-9 after the reaction is finished, and concentrating the solution to obtain a polyvinyl alcohol embolism microsphere intermediate;
S2, preparing embolic microspheres capable of slowly releasing the drugs: adding the intermediate of the polyvinyl alcohol embolism microsphere prepared in the step S1, molecules of the slow-release drug, a cross-linking agent and an initiator into water for dissolution, then adding a solvent and a surfactant, then adding organic base as a second catalyst in inert gas atmosphere, and washing after the reaction is finished to obtain the embolism microsphere of the slow-release drug;
The water-soluble molecule is at least one of N- (2, 2-dimethoxy ethyl) -2-acrylamide, 4-acrylamido butyraldehyde dimethyl acetal and N-acrylamido acetaldehyde;
The cross-linking agent is at least one selected from 2-acrylamide-2-methylpropanesulfonic acid, 2-acrylamide-2-methylpropanesulfonic acid sodium, 3-sulfopropyl potassium acrylate and 3-sulfopropyl potassium methacrylate;
The molecule of the slow-release medicine is at least one selected from sodium p-styrenesulfonate, potassium p-styrenesulfonate, sodium cinnamate and potassium cinnamate.
5. The method according to claim 4, wherein the polyvinyl alcohol in step S1 has a weight average molecular weight of 30000 to 80000.
6. The method according to claim 4, wherein the mass ratio of the polyvinyl alcohol, the water-soluble molecule containing an unsaturated bond and an aldehyde or acetal structure, and the first catalyst in step S1 is 1: (0.01-0.5): (0.05-5).
7. The method according to claim 4, wherein the initiator in step S2 is at least one selected from the group consisting of potassium persulfate, ammonium persulfate, and sodium persulfate.
8. The preparation method according to claim 4, wherein the mass ratio of the intermediate of the polyvinyl alcohol embolic microsphere, the molecule of the slow-release drug, the crosslinking agent, the initiator, the water, the solvent, the surfactant and the second catalyst in the step S2 is 1: (0.01-0.5): (0.001-0.2): (0.0001-0.05): (0.1-3): (4-50): (0.001-0.1): (0.0001-0.05).
9. The method of claim 4, wherein the first catalyst is concentrated hydrochloric acid or concentrated sulfuric acid; the solvent in the S2 is at least one of butyl acetate, ethyl acetate, liquid paraffin, castor oil, soybean oil, n-heptane or cyclohexane; the surfactant is at least one of cellulose acetate butyrate, cellulose acetate, span 20, span 80, tween 20 and tween 80; the second catalyst is at least one of tetramethyl ethylenediamine, triethylamine and N, N-dimethylaniline.
10. The preparation method according to claim 4, wherein the reaction temperature in the step S1 is 10-35 ℃ and the reaction time is 3-8 hours; the reaction temperature in the step S2 is 55-65 ℃ and the reaction time is 2-6h.
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