CN101265304B - Bionic chitosan derivatives, preparation method thereof and lipoid plastid preparation containing the same - Google Patents
Bionic chitosan derivatives, preparation method thereof and lipoid plastid preparation containing the same Download PDFInfo
- Publication number
- CN101265304B CN101265304B CN2008100239040A CN200810023904A CN101265304B CN 101265304 B CN101265304 B CN 101265304B CN 2008100239040 A CN2008100239040 A CN 2008100239040A CN 200810023904 A CN200810023904 A CN 200810023904A CN 101265304 B CN101265304 B CN 101265304B
- Authority
- CN
- China
- Prior art keywords
- preparation
- coo
- chitosan derivatives
- chitosan
- phosphorylcholine
- 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.)
- Expired - Fee Related
Links
- 229920001661 Chitosan Polymers 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title abstract description 31
- 239000011664 nicotinic acid Substances 0.000 title abstract description 5
- 210000002706 plastid Anatomy 0.000 title description 3
- 239000003814 drug Substances 0.000 claims abstract description 22
- 238000006467 substitution reaction Methods 0.000 claims description 8
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 7
- 229960003668 docetaxel Drugs 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000006196 deacetylation Effects 0.000 claims description 4
- 238000003381 deacetylation reaction Methods 0.000 claims description 4
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 2
- 229960001592 paclitaxel Drugs 0.000 claims description 2
- 125000002456 taxol group Chemical group 0.000 claims 1
- 239000002502 liposome Substances 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 11
- 229920000642 polymer Polymers 0.000 abstract description 4
- 239000003937 drug carrier Substances 0.000 abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 125000004423 acyloxy group Chemical group 0.000 description 18
- 125000005395 methacrylic acid group Chemical group 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 9
- 150000003904 phospholipids Chemical class 0.000 description 9
- 229950004354 phosphorylcholine Drugs 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- -1 2,4-octadecadienoyl groups Chemical group 0.000 description 7
- ITPZJMFZIDUUGX-UHFFFAOYSA-O C(CCCCCCCCC)P(=O)=C(O)C[N+](C)(C)C Chemical compound C(CCCCCCCCC)P(=O)=C(O)C[N+](C)(C)C ITPZJMFZIDUUGX-UHFFFAOYSA-O 0.000 description 7
- QCDSEQXIYMEZMJ-UHFFFAOYSA-O CCP(=O)=C(O)C[N+](C)(C)C Chemical compound CCP(=O)=C(O)C[N+](C)(C)C QCDSEQXIYMEZMJ-UHFFFAOYSA-O 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- VLCAYQIMSMPEBW-UHFFFAOYSA-N methyl 3-hydroxy-2-methylidenebutanoate Chemical compound COC(=O)C(=C)C(C)O VLCAYQIMSMPEBW-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 150000005846 sugar alcohols Polymers 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CRDNMYFJWFXOCH-YPKPFQOOSA-N (3z)-3-(3-oxo-1h-indol-2-ylidene)-1h-indol-2-one Chemical compound N/1C2=CC=CC=C2C(=O)C\1=C1/C2=CC=CC=C2NC1=O CRDNMYFJWFXOCH-YPKPFQOOSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 2
- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- COVMVPHACFXMAX-OYNOKLRGSA-N (-)-morellic acid Chemical compound C1=CC(C)(C)OC2=C1C(O)=C1C(=O)C3=C[C@@H](C(=O)[C@]4(C\C=C(\C)C(O)=O)OC5(C)C)C[C@@H]5[C@]34OC1=C2CC=C(C)C COVMVPHACFXMAX-OYNOKLRGSA-N 0.000 description 1
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 1
- ZSZRUEAFVQITHH-UHFFFAOYSA-N 2-(2-methylprop-2-enoyloxy)ethyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CC(=C)C(=O)OCCOP([O-])(=O)OCC[N+](C)(C)C ZSZRUEAFVQITHH-UHFFFAOYSA-N 0.000 description 1
- RWLALWYNXFYRGW-UHFFFAOYSA-N 2-Ethyl-1,3-hexanediol Chemical compound CCCC(O)C(CC)CO RWLALWYNXFYRGW-UHFFFAOYSA-N 0.000 description 1
- SBMUNILHNJLMBF-UHFFFAOYSA-N 2-chloro-1,3,2$l^{5}-dioxaphospholane 2-oxide Chemical compound ClP1(=O)OCCO1 SBMUNILHNJLMBF-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- 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 description 1
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 1
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- CRDNMYFJWFXOCH-BUHFOSPRSA-N Couroupitine B Natural products N\1C2=CC=CC=C2C(=O)C/1=C1/C2=CC=CC=C2NC1=O CRDNMYFJWFXOCH-BUHFOSPRSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 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 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- HAVJATCHLFRDHY-UHFFFAOYSA-N Harringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HAVJATCHLFRDHY-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- XNIZIBPYBUCVEU-UHFFFAOYSA-N Morellic acid Natural products CC1Oc2c(CC=C(C)C)c3OC45C6CC(C=C4C(=O)c3c(O)c2C=C1)C(=O)C5(CC=C(C)/C(=O)O)OC6(C)C XNIZIBPYBUCVEU-UHFFFAOYSA-N 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 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 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- INSRQEMEVAMETL-UHFFFAOYSA-N decane-1,1-diol Chemical compound CCCCCCCCCC(O)O INSRQEMEVAMETL-UHFFFAOYSA-N 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960005082 etohexadiol Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- HAVJATCHLFRDHY-JZTSUELASA-N harringtonine Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@](O)(CCC(C)(C)O)CC(=O)OC)[C@@H]4C2=CC2=C1OCO2 HAVJATCHLFRDHY-JZTSUELASA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000013002 intravenous (IV) drug Substances 0.000 description 1
- CRDNMYFJWFXOCH-UHFFFAOYSA-N isoindigotin Natural products N1C2=CC=CC=C2C(=O)C1=C1C2=CC=CC=C2NC1=O CRDNMYFJWFXOCH-UHFFFAOYSA-N 0.000 description 1
- COVMVPHACFXMAX-ZVKSWBPMSA-N isomorellic acid Natural products O=C(O)/C(=C\C[C@]12C(=O)[C@H]3C=C4C(=O)c5c(O)c6c(c(C/C=C(\C)/C)c5O[C@]14[C@@H](C(C)(C)O2)C3)OC(C)(C)C=C6)/C COVMVPHACFXMAX-ZVKSWBPMSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 1
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 1
- SDHTXBWLVGWJFT-XKCURVIJSA-N oridonin Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12[C@@H](O)CCC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 SDHTXBWLVGWJFT-XKCURVIJSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229940061969 rheumatrex Drugs 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 229930185378 rubescensin Natural products 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 description 1
- 229960004245 silymarin Drugs 0.000 description 1
- 235000017700 silymarin Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960002190 topotecan hydrochloride Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin 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)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Cosmetics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the field of polymer chemistry and pharmaceutical excipients. The invention specifically relates to a type of bionic chitosan derivatives (I), which can form liposomes with drugs; and the invention further discloses a preparation method thereof and relates to functions as the different types of drug carriers.
Description
Technical field
The present invention relates to polymer chemistry and field of pharmaceutical excipients.Be specifically related to a class bionic chitosan derivatives, especially can form chitosan derivatives of lipoid plastid and preparation method thereof, also relate to it as the effect of dissimilar pharmaceutical carriers and contain its pharmaceutical composition.
Background technology
Liposome has obtained successful Application on clinical disease treatment, it is not only the carrier of medicine, simultaneously in the prolong drug body-internal-circulation time, improve drug targeting, realize that cytolemma merges, improves curative effect, reduces aspects such as toxic side effect and all play an important role.But; liposome by the natural phospholipid preparation easily presents unstable physics or chemistry in seasoning; produce phenomenons such as gathering, oxidation, drug leakage, its major cause is that hydrolysis reaction or oxidizing reaction easily take place structural ester bond of main component phosphatidylcholine and the unsaturated acyl group in the phosphatide.
In solving liposome unstable scheme, the application of polymerized liposome (polymerized liposome) is a kind of new research trend.After bibliographical information is made liposome with the phosphatidylcholine that contains two keys or two sulphur rings in the structure, through the gamma-rays radiation, cause unsaturated phosphatide generation polymerization or carry out ring-opening polymerization, obtained stable polymerized liposome (M Jung, I Ouden, AMontoya-Goni, DHW Hubert, P M Frederik, AM van Herk, AL German.Polymerization in polymerizable vesiclebilayer membranes.Langmuir.2000,16,4185-4195.K Aakama, K Awai, Y Yano.In vitro and in vivo stabilityof polymerized mixed liposomes composed of 2,4-octadecadienoyl groups of phospholipids.Polym Adv Technol.2001,11:280-287.).But this method easily makes the medicine that is embedded in the liposome suffer damage when polymerization, and polymeric reaction condition is relatively harsher.
The polymkeric substance (phospholipid analogouspolymers) of biomimetic type phospholipid polyalcohol (phospholipid polymers) and phospholipid analogues is subjected to paying close attention to widely since the seventies in last century owing to its application aspect the microbial film structure.Synthetic so far and studied the phospholipid polyalcohol material (T.Nakaya that several big classes such as polyamino acid phosphatide, urethane phosphatide, organopolysiloxane phosphatide, polyethylene base class phosphatide can form the bilayer structure, J.L.Yu.Phospholipid polymers.Prog.Polym.Sci.1999,24:143-181.).
Summary of the invention
The invention discloses the new bionic chitosan derivatives I of a class, is skeleton with the chitosan, at its 2-NH
2(2-methacryloyl-oxyethyl phosphorylcholine, derivative MPC) form a kind of novel phospholipid polyalcohol to the similar thing of grafting phosphatidylcholine-2-methacryloxyethyl Phosphorylcholine, and utilize it to make up liposome.Its inside has aqueous favoring concurrently with mutually hydrophobic, can satisfy the medicine carrying requirement of dissimilar medicines, and has the characteristics of sterically stabilized liposome.
R
1=H or CH
2COOH
Viscosity-average molecular weight 2k-30 ten thousand, and the R substitution value is 10-80%; Deacetylation 55-92%; N=2-12.
The preferred 15-77% of R substitution value of general formula I chitosan derivatives, the preferred 50-92% of deacetylation.
N preferred 2,5,8,10 or 12.
The synthetic route of chitosan derivatives of the present invention is:
Chitosan derivatives of the present invention be white to yellow powder, the chitosan derivatives of molecular weight 2,000 to 30,000 is soluble in water, the chitosan derivatives of molecular weight more than 30,000 is dissolved in 0.1% glacial acetic acid solution.All can form liposome in the solution, its particle diameter is between 200-400nm.
The present invention, carries out chemical structure and modifies as raw material with the chitosan of biodegradable natural origin, makes it form the phospholipid polyalcohol that has hydrophilic section and water delivery section simultaneously, spontaneous formation liposome in water.Be suitable for medicine, with drug matching or as pharmaceutical carrier, especially can be as the excellent carrier of intravenous (IV) drug.For example for Docetaxel, its peak concentration in liposome is 1.8mg/ml, is 250 times of solubleness in its water.
The invention also discloses a kind of pharmaceutical composition, it contains medicine and chitosan derivatives of the present invention.Described medicine can be water miscible, also can be insoluble.Insoluble drug can be: camptothecin (as camptothecine, 10-hydroxycamptothecine, 9-nitrocamptothecin, SN-38 etc.), taxol, Docetaxel, ciclosporin A, etoposide, teniposide, Etoposide, vindesine, nimodipine, nifedipine, nitrendipine, Zorubicin, daunorubicin, mitomycin, Rheumatrex, rubescensin, morellic acid, harringtonine, homoharringtonine, Breviscarpine, bilobalide, silymarin, Indirubin.Water soluble drug can be Walaphage, doxorubicin hydrochloride, vincristine sulphate, berberine hydrochloride, daunorubicin hydrochloride, topotecan hydrochloride etc.Also can form Liposomal formulation in addition with bio-pharmaceutical such as nucleic acid and protein drug (as Regular Insulin etc.).Chitosan derivatives of the present invention all has good solublization by spontaneous formation liposome in water to above-mentioned insoluble drug.In addition, utilize the chitosan derivatives of invention, water soluble drug also can be prepared into liposome at an easy rate.The weight ratio of said medicine and chitosan derivatives of the present invention is 1: during 1-10, solubilizing effect is relatively good, also is fit to be prepared into various pharmaceutical preparations.
Embodiment:
Cm-chitosan deacetylation 55%, carboxylation degree 90%, viscosity-average molecular weight 70KD; Deacetylating degree of chitosan 88%, viscosity-average molecular weight 3KD; Reagent is chemical pure and analytical pure, and the molecular weight cut-off of dialysis tubing is 10000 (MWCO10000).
Embodiment 1
1.2-chloro-1,3, the preparation of 2-dioxaphospholane (CDP)
Add anhydrous phosphorus trichloride 220ml and 500ml methylene dichloride in the three-necked bottle, stir, slowly drip ethylene glycol simultaneously.Dropwise, heating in water bath rotary evaporation steaming vibrating dichloromethane, residual liquid water pump underpressure distillation obtains 2-chloro-1,3, the 2-dioxaphospholane.Product is a colourless transparent liquid, 89 ℃ of boiling points (96Kpa), productive rate 74.5%.
2.2-chloro-2-oxo-1,3, synthetic (COP) of 2-dioxaphospholane
Add the 350ml dry-out benzene in the three-necked bottle, 235.6g2-chloro-1,3, the 2-dioxaphospholane feeds exsiccant oxygen, reaction 24h.The reaction solution rotary evaporation boils off benzene, and underpressure distillation gets 2-chloro-2-oxo-1,3,2-dioxaphospholane.Product is a colourless transparent liquid, 92 ℃ of boiling points (30Pa), productive rate 62.3%.
3. the preparation of hydroxyethyl methylacrylate
Add the tetrahydrofuran (THF) that 73.6g ethylene glycol and 650ml heavily steam in the three-necked bottle, be heated to 50 ℃ ethylene glycol and tetrahydrofuran (THF) are mixed, be chilled to 10 ℃ again, in reaction solution, add the 24.6g triethylamine fast, stir, the 114.95g acrylate chloride slowly is added drop-wise in the reaction solution with constant pressure funnel.After dropwising, 10-15 ℃ of reaction 0.5h stirs ambient temperature overnight.The reaction solution suction filtration, filtrate decompression concentrates, and adds 500ml ethanol in solid residue, behind the stirring at room 0.5h, filters, and filtrate is chilled to 0 ℃, crystallization, the reactant crude product of suction filtration.The reactant crude product is refining with ethanol, gets colourless liquid (hydroxyethyl methylacrylate): 123.2g, and productive rate is 57.2%.
4. methacrylic acyloxy ethyl Phosphorylcholine is synthetic
Add 43.5g hydroxyethyl methylacrylate, 38.2g triethylamine and 650ml acetonitrile in the three-necked bottle, cryosel is bathed and is cooled to-10 ℃, slowly drip 48g2-chloro-2-oxo-1,3, the 100ml acetonitrile solution of 2-dioxaphospholane, be warming up to 0 ℃ after dripping and continue to stir 1h, the elimination solid, filtrate decompression boils off acetonitrile, obtains light yellow viscous liquid, be transferred in the pressure bottle, add the acetonitrile 300ml that contains the 30g Trimethylamine 99, airtight 50 ℃ are reacted 16h down, have reacted the pressure reducing and steaming solvent, obtain light yellow viscous liquid 75.37g, productive rate is 84%.
5. methacrylic acyloxy ethyl Phosphorylcholine grafting cm-chitosan (cmcs-2)
Take by weighing the 1g cm-chitosan and be dissolved in 1% the acetum, add the methacrylic acyloxy ethyl Phosphorylcholine that 2.63g goes up step gained 84%, 60 ℃ of constant temperature, reaction 6h, cooling, dialysis 48h, freeze-drying, white solid.
cmcs-2：
FT-IR：2939.5，1726.3，1630.3，1410.0，1324.6，1246.4，1061.6.
1H?NMR(500MHz，D
2O)：4.8(H
1)，4.3(O-C
H 2-COOH)，4.0(O-CH
2C
H 2-N
+)，3.9-3.5(H
2，H
3，H
4，H
5，H
6)，3.8(O-CH
2CH
2-O)，3.7(O-C
H 2CH
2-N
+)，3.3(N
+(CH
3)
3)，2.9(NH-C
H 2-CH(CH
3)-COO)，2.0-1.9(NH-CH
2-C
H(CH
3)-COO，NH-CO-C
H 3)，1.3(NH-CH
2-CH(C
H 3)-COO).
13C?NMR(500MHz，D
2O)：178.4(NH-
CO-CH
3)，174.3(CH(CH
3)-
COO)，173.5(O-CH
2-
COOH)，98.8(C
1)，79.4(C
4)，75.8(C
5)，72.3(NH-CH
2-O-
CH
2-COOH)，71.2(C
3)，68.7(C
6)，64.1(O-CH
2 CH
2-N
+)，63.0(O-
CH
2CH
2-N
+)，62.0(O-CH
2-CH
2-O)，58.0(C
2)，56.8(N
+(CH
3)
3)，49.4(NH-
CH
2-CH(CH
3)-COO)，32.2(NH-CH
2-
CH(CH
3)-COO)，31.4(NH-CO-
CH
3)，24.9(NH-CH
2-CH(
CH
3)-COO).
According to the data of cmcs-2 ultimate analysis, the substitution value that can calculate methacrylic acyloxy ethyl Phosphorylcholine is 74.9%.
Embodiment 2
1. the preparation of methacrylic acid hydroxy pentane ester
React with pentanediol and tetrahydrofuran (THF), triethylamine, the preparation method is with the preparation of hydroxyethyl methylacrylate among the embodiment 1.
2. methacrylic acyloxy amyl group Phosphorylcholine is synthetic
Make with methacrylic acid hydroxy pentane ester and COP reaction, the preparation method is with the preparation of methacrylic acyloxy ethyl Phosphorylcholine among the embodiment 1.
3. methacrylic acyloxy amyl group Phosphorylcholine grafting cm-chitosan (cmcs-5)
With methacrylic acyloxy amyl group Phosphorylcholine and cm-chitosan reaction, the preparation method is with the preparation of cmcs-2 among the embodiment 1.
cmcs-5：
FT-IR：2939.5，1722.8，1637.4，1406.4，1317.5，1317.5，1065.2.
1H?NMR(500MHz，D
2O)：4.9(H
1)，4.2(O-C
H 2-COOH)，4.0(O-CH
2C
H 2-N
+)，4.0-3.6(H
2，H
3，H
4，H
5，H
6)，3.8(O-C
H 2CH
2-N
+)，3.6(O-C
H 2-(CH
2)
3-C
H 2-O)，3.2(N
+(CH
3)
3)，2.9(NH-C
H 2-CH(CH
3)-COO)，2.2(NH-CH
2-C
H(CH
3)-COO)，2.0(NH-CO-C
H 3)，1.7-1.2(O-CH
2-(C
H 2)
3-CH
2-O)，1.4(NH-CH
2-CH(C
H 3)-COO).
13C?NMR(500MHz，D
2O)：178.9(NH-
CO-CH
3)，177.3(NH-CH
2-CH(CH
3)-
COO)，173.7(O-CH
2-
COOH)，100.3(C
1)，79.5(C
4)，77.7(C
5)，76.5(O-
CH
2-COOH)，72.4(C
3)，68.8(C
6)，64.3(O-CH
2 CH
2-N
+)，63.3(O-
CH
2CH
2-N
+)，62.0(O-
CH
2-(CH
2)
3-
CH
2-O)，58.3(C
2)，49.4(N
+(CH
3)
3)，47.4(NH-
CH
2-CH(CH
3)-COO)，32.1(NH-CH
2-
CH(CH
3)-COO)，30.0(NH-CO-
CH
3)，26.5-24.6(O-CH
2-(
CH
2)
3-CH
2-O，NH-CH
2-CH(
CH
3)-COO).
According to the data of cmcs-5 ultimate analysis, the substitution value that can calculate methacrylic acyloxy amyl group Phosphorylcholine is 28.4%.
Embodiment 3
1. the preparation of hydroxyethyl methacrylate monooctyl ester
React with ethohexadiol and tetrahydrofuran (THF), triethylamine, the preparation method is with the preparation of hydroxyethyl methylacrylate among the embodiment 1.
2. methacrylic acyloxy octyl group Phosphorylcholine is synthetic
Make with hydroxyethyl methacrylate monooctyl ester and COP reaction, the preparation method is with the preparation of methacrylic acyloxy ethyl Phosphorylcholine among the embodiment 1.
3. methacrylic acyloxy octyl group Phosphorylcholine grafting cm-chitosan (cmcs-8)
With methacrylic acyloxy octyl group Phosphorylcholine and cm-chitosan reaction, the preparation method is with the preparation of cmcs-2 among the embodiment 1.
cmcs-8：
FT-IR：2930.8，1737.3，1641.0，1403.7，1342.8，1239.3，1065.4.
1H?NMR(500MHz，D
2O)：4.9(H
1)，4.2-3.6(H
2，H
3，H
4，H
5，H
6)，4.1(O-C
H 2-COOH)，3.8(O-CH
2C
H 2-N
+)，3.7(O-C
H 2CH
2-N
+)，3.6(O-C
H 2-(CH
2)
6-C
H 2-O)，3.2(N
+(CH
3)
3)，2.9(NH-C
H 2-CH(CH
3)-COO)，2.7(NH-CH
2-C
H(CH
3)-COO)，2.0(NH-CO-C
H 3)，1.7-1.2(O-CH
2-(C
H 2)
6-CH
2-O)，1.3(NH-CH
2-CH(C
H 3)-COO).
13C?NMR(500MHz，D
2O)：178.1(NH-
CO-CH
3)，175.0(NH-CH
2-CH(CH
3)-
COO)，169.6(O-CH
2-
COOH)，100.7(C
1)，79.4(C
4)，77.0(C
5)，75.5(O-
CH
2-COOH)，71.7(C
3)，68.7(C
6)，64.3(O-CH
2 CH
2-N
+)，63.1(O-
CH
2CH
2-N
+)，62.0(O-
CH
2-(CH
2)
6-
CH
2-O)，58.0(C
2)，51.2(N
+(CH
3)
3)，47.4(NH-
CH
2-CH(CH
3)-COO)，31.3(NH-CH
2-
CH(CH
3)-COO)，28.0(NH-CO-
CH
3)，27.6-24.9(O-CH
2-(
CH
2)
6-CH
2-O，NH-CH
2-CH(
CH
3)-COO).
According to the data of cmcs-8 ultimate analysis, the substitution value that can calculate methacrylic acyloxy octyl group Phosphorylcholine is 19.2%.
Embodiment 4
1. the preparation of hydroxyethyl methacrylate ester in the last of the ten Heavenly stems
React with decanediol and tetrahydrofuran (THF), triethylamine, the preparation method is with the preparation of hydroxyethyl methylacrylate among the embodiment 1.
2. methacrylic acyloxy decyl Phosphorylcholine is synthetic
Make with hydroxyethyl methacrylate ester in the last of the ten Heavenly stems and COP reaction, the preparation method is with the preparation of methacrylic acyloxy ethyl Phosphorylcholine among the embodiment 1.
3. methacrylic acyloxy decyl Phosphorylcholine grafting cm-chitosan (cmcs-10)
With methacrylic acyloxy decyl Phosphorylcholine and cm-chitosan reaction, the preparation method is with the preparation of cmcs-2 among the embodiment 1.
cmcs-10：
FT-IR：2925.3，1726.3，1637.4，1473.9，1378.0，1232.2，1082.9.
1H?NMR(500MHz，D
2O)：5.1(H
1)，4.2(O-C
H 2-COOH)，4.0(O-CH
2C
H 2-N
+)，4.0-3.4(H
2，H
3，H
4，H
5，H
6)，3.8(O-C
H 2CH
2-N
+)，3.7(O-C
H 2-(CH
2)
8-C
H 2-O)，3.2(N
+(CH
3)
3)，2.9(NH-C
H 2-CH(CH
3)-COO)，2.7(NH-CH
2-C
H(CH
3)-COO)，2.0(NH-CO-C
H 3)，1.6-1.2(O-CH
2-(C
H 2)
8-CH
2-O)，1.3(NH-CH
2-CH(C
H 3)-COO).
13C?NMR(500MHz，D
2O)：177.1(NH-
CO-CH
3)，174.6(CH(CH
3)-
COO)，169.6(O-CH
2-
COOH)，100.1(C
1)，79.2(C
4)，77.0(C
5)，72.0(NH-CH
2-O-
CH
2-COOH)，71.2(C
3)，68.8(C
6)，64.3(O-CH
2 CH
2-N
+)，62.6(O-
CH
2CH
2-N
+)，62.0(O-
CH
2-(CH
2)
6-
CH
2-O)，59.0(C
2)，56.8(N
+(CH
3)
3)，49.4(NH-
CH
2-CH(CH
3)-COO)，33.1(NH-CH
2-
CH(CH
3)-COO)，29.3(NH-CO-
CH
3)，28.3-24.9(O-CH
2-(
CH
2)
8-CH
2-O，NH-CH
2-CH(
CH
3)-COO).
According to the data of cmcs-10 ultimate analysis, the substitution value that can calculate methacrylic acyloxy decyl Phosphorylcholine is 19.3%.
Embodiment 5:
1. methacrylic acyloxy decyl Phosphorylcholine grafted chitosan (mpc 10-cs)
With methacrylic acyloxy decyl Phosphorylcholine and chitosan reaction, the preparation method is with the preparation of cmcs-2 among the embodiment 1.
mpc10-cs：
FT-IR：2931.8，1715.6，1659.4，1481.0，1381.5，1213.9，1040.6.
1H?NMR(500MHz，D
2O)：4.5(H
1)，4.2(O-C
H 2CH
2-N
+)，3.9(O-C
H 2-(CH
2)
8-C
H 2-O)，3.9-3.4(H
2，H
3，H
4，H
5，H
6)，3.5(O-CH
2C
H 2-N
+)，3.1(N
+(CH
3)
3)，2.8(NH-C
H 2-CH(CH
3)-COO)，2.1(NH-CH
2-C
H(CH
3)-COO)，1.9(NH-CO-C
H 3)，1.5-1.2(O-CH
2-(C
H 2)
8-CH
2-O，NH-CH
2-CH(C
H 3)-COO).
13C?NMR(500MHz，D
2O)：177.3(NH-CH
2-CH(CH
3)-
COO)，100.4(C
1)，79.2(C
4)，77.5(C
5)，72.3(C
3)，64.0(C
6)，63.0(O-CH
2 CH
2-N
+)，62.7(O-
CH
2CH
2-N
+)，62.0(O-
CH
2-(CH
2)
8-
CH
2-O)，56.7(C
2)，50.1(NH-
CH
2-CH(CH
3)-COO)，32.5(NH-CH
2-
CH(CH
3)-COO)，31.0-24.9(O-CH
2-(
CH
2)
8-CH
2-O，NH-CH
2-CH(
CH
3)-COO).
According to the data of mpc-cs ultimate analysis, the substitution value that can calculate methacrylic acyloxy decyl Phosphorylcholine is 76.4%.
Embodiment 6
N-2-methyl-prop acyloxy decyl phosphatidylcholine-chitosan (mpc10-cs) solubilising Docetaxel
20mgN-2-methyl-prop acyloxy ethyl phosphatidylcholine-chitosan (prepared among the embodiment 5) is dissolved in the 2ml distilled water, simultaneously the 4mg Docetaxel is dissolved in the 0.2ml dehydrated alcohol, both mix ultrasonic 30min, distill water dialysis 12h, 0.8 μ m filtering with microporous membrane obtains the Docetaxel liposome solutions.Measuring solution Chinese traditional medicine content with the HPLC method is 0.26mg/ml.
Embodiment 7:
The mensuration of particle diameter
Carboxymethyl chitosan derivative and docetaxel freeze-drying product 30mg thereof that different carbon chain is long are dissolved in the 3ml pure water, use Zetasizer 3000HS instrument (Malvern Instruments behind the ultrasonic 30min of room temperature, Malvern, UK) at 633nm, 25 ℃, He-Ne laser determination particle diameter.The results are shown in Table 1
Table 1: the long carboxymethyl chitosan derivative particle diameter (nm) of different carbon chain
| Derivative | cmcs-2 | cmcs-5 | cmcs-8 | cmcs-10 |
| Particle diameter | 319.7 | 360.8 | 412.2 | 430.4 |
Claims (5)
1. the chitosan derivatives of following structural I:
R wherein
1=H or CH
2COOH
Viscosity-average molecular weight 2,000-300,000, R substitution value are 10-80%; Deacetylation 55-92%; N=2-12.
2. the chitosan derivatives of claim 1, wherein n=2,5,8,10 or 12.
3. pharmaceutical composition wherein contains the chitosan derivatives of medicine and claim 1.
4. the pharmaceutical composition of claim 3, its Chinese traditional medicine is selected from taxol, Docetaxel or camptothecine.
5. the pharmaceutical composition of claim 4, the weight ratio of its Chinese traditional medicine and chitosan derivatives is 1: 1-10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100239040A CN101265304B (en) | 2008-04-18 | 2008-04-18 | Bionic chitosan derivatives, preparation method thereof and lipoid plastid preparation containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100239040A CN101265304B (en) | 2008-04-18 | 2008-04-18 | Bionic chitosan derivatives, preparation method thereof and lipoid plastid preparation containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101265304A CN101265304A (en) | 2008-09-17 |
| CN101265304B true CN101265304B (en) | 2011-08-10 |
Family
ID=39988012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100239040A Expired - Fee Related CN101265304B (en) | 2008-04-18 | 2008-04-18 | Bionic chitosan derivatives, preparation method thereof and lipoid plastid preparation containing the same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101265304B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646201A (en) * | 2015-12-30 | 2016-06-08 | 潍坊科麦化工有限公司 | Synthesis method of acetoacetoxyethyl methacrylate |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102424692B (en) * | 2011-12-16 | 2012-11-07 | 常熟富士莱医药化工有限公司 | Preparation method for 2-chloro-2-oxo-1,3,2-dioxaphospholane |
| CN105384835A (en) * | 2015-11-11 | 2016-03-09 | 暨南大学 | Choline diphosphate chitosan salt and application thereof |
| JP7102423B2 (en) * | 2017-02-16 | 2022-07-19 | イェダ リサーチ アンド ディベロップメント カンパニー リミテッド | Liposomal drug delivery vehicle |
| CN107056834B (en) * | 2017-04-06 | 2019-02-15 | 苏州怡彼得生物技术有限公司 | A kind of synthetic method of artificial cell membrane's principal component 2- methylacryoyloxyethyl Phosphorylcholine |
| CN107903341B (en) * | 2017-07-27 | 2019-12-13 | 大连民族大学 | Application of double-aliphatic-chain substituent phosphatidyl ethanolamine chitosan |
| CN107474160B (en) * | 2017-08-10 | 2019-05-28 | 山东师范大学 | A kind of Phosphorylcholine base polyethylene glycol-chitosan and preparation method thereof |
| CN110551235A (en) * | 2019-09-12 | 2019-12-10 | 西南交通大学 | Water-soluble modified chitosan and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1962701A (en) * | 2006-11-24 | 2007-05-16 | 暨南大学 | Phosphoryl choline chitosan derivative synthesis method |
-
2008
- 2008-04-18 CN CN2008100239040A patent/CN101265304B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1962701A (en) * | 2006-11-24 | 2007-05-16 | 暨南大学 | Phosphoryl choline chitosan derivative synthesis method |
Non-Patent Citations (2)
| Title |
|---|
| 曾戎.磷酰化壳聚糖仿生衍生物的合成及其与DNA的相互作用.暨南大学学报29 1.2008,29(1),85-89. |
| 曾戎.磷酰化壳聚糖仿生衍生物的合成及其与DNA的相互作用.暨南大学学报29 1.2008,29(1),85-89. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646201A (en) * | 2015-12-30 | 2016-06-08 | 潍坊科麦化工有限公司 | Synthesis method of acetoacetoxyethyl methacrylate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101265304A (en) | 2008-09-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101265304B (en) | Bionic chitosan derivatives, preparation method thereof and lipoid plastid preparation containing the same | |
| CN101401941B (en) | Preparation and uses of tumor-targeted carrier material RGD-fatty alcohol series of compounds | |
| Guo et al. | pH-triggered intracellular release from actively targeting polymer micelles | |
| CN102114246B (en) | Amphiphilic polysaccharide derivative vector for specific medicine release in organism focusas well as preparation and application of pharmaceutical composition thereof | |
| CN101775082B (en) | Amphoteric ion-based charge reversal chitosan derivative and application thereof in medicament | |
| CN105283441B (en) | Disulfide for delivering medicament | |
| Patra et al. | Retracted Article: The next generation cell-penetrating peptide and carbon dot conjugated nano-liposome for transdermal delivery of curcumin | |
| CN105997880B (en) | A kind of anti-tumor nano drug and preparation method thereof based on crosslinked bio degradable polymer vesica | |
| US20120039983A1 (en) | Amphiphilic macromolecule-lipid complexes | |
| CN101745119A (en) | Polysaccharide conjugate of carboxylic acid drug, preparation method thereof and application thereof | |
| CN103301472A (en) | Amphiphilic polysaccharide-anti-tumor medicament conjugate capable of releasing medicines specifically at lesion site of living body, as well as preparation method and application of medicinal composition of amphiphilic polysaccharide-anti-tumor medicament conjugate | |
| CN103435718B (en) | The hyaluronic acid cholesteryl ester that PEG modifies | |
| CN101878024A (en) | The taxane delivery system of improvement | |
| AU2016374669A1 (en) | Biodegradable amphiphilic polymer, polymer vesicle prepared therefrom and use in preparing target therapeutic medicine for lung cancer | |
| Wang et al. | Efficacy of dual-functional liposomes containing paclitaxel for treatment of lung cancer Retraction in/10.3892/or. 2017.6006 | |
| CN101991860A (en) | Poloxamer-carboxylic acid drug conjugate and preparation method and application thereof | |
| Hardiansyah et al. | Novel pH-sensitive drug carriers of carboxymethyl-hexanoyl chitosan (Chitosonic® Acid) modified liposomes | |
| Cai et al. | Bioinspired mimics: Self-assembly of redox-activated phosphorylcholine–based biodegradable copolymers for enhancing antitumor efficiency | |
| Zhang et al. | Fmoc-conjugated PEG-vitamin E 2 micelles for tumor-targeted delivery of paclitaxel: enhanced drug-carrier interaction and loading capacity | |
| CN107266384B (en) | N- carboxyl inner-acid anhydride monomer and polyaminoacid based on 2- aminohexadecanoic acid and preparation method thereof | |
| CN103370329A (en) | Amphiphilic cyclic phosphazene trimer, hydrophobic pharmaceutical formulation micellized by amphiphilic cyclic phosphazene trimer, and preparation methods thereof | |
| CN107998081A (en) | A kind of application for targeting reduction response vesica Nano medication in treatment of brain tumor medicine is prepared | |
| CN101602791B (en) | Integrin receptor target lipidosome drug carrier, preparation method and application thereof | |
| Gao et al. | Hydrotropic polymer-based paclitaxel-loaded self-assembled nanoparticles: preparation and biological evaluation | |
| CN105963708B (en) | A kind of phosphatidyl nano-prodrug and its preparation method and application of enzymatic response release |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110810 |