CA1167838A - Polymerizable phospholipids and a process for their preparation, polymeric phospholipids and a process for their preparation, and the use of the polymeric phospholipids - Google Patents
Polymerizable phospholipids and a process for their preparation, polymeric phospholipids and a process for their preparation, and the use of the polymeric phospholipidsInfo
- Publication number
- CA1167838A CA1167838A CA000373059A CA373059A CA1167838A CA 1167838 A CA1167838 A CA 1167838A CA 000373059 A CA000373059 A CA 000373059A CA 373059 A CA373059 A CA 373059A CA 1167838 A CA1167838 A CA 1167838A
- Authority
- CA
- Canada
- Prior art keywords
- radical
- phospholipid
- denotes
- glycerol
- benzyl
- 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
Links
- 150000003904 phospholipids Chemical class 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims abstract description 43
- 230000008569 process Effects 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 150000003254 radicals Chemical class 0.000 claims description 61
- 150000001875 compounds Chemical class 0.000 claims description 37
- -1 alkyl radical Chemical class 0.000 claims description 33
- 239000000126 substance Substances 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 6
- 125000003158 alcohol group Chemical group 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- 229920005862 polyol Polymers 0.000 claims description 5
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 4
- 229940107161 cholesterol Drugs 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 claims description 4
- 238000006266 etherification reaction Methods 0.000 claims description 4
- IRHTZOCLLONTOC-UHFFFAOYSA-N hexacosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCO IRHTZOCLLONTOC-UHFFFAOYSA-N 0.000 claims description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 150000001414 amino alcohols Chemical class 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 150000003077 polyols Chemical class 0.000 claims description 3
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 2
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 claims description 2
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 2
- ZESKRVSPQJVIMH-UHFFFAOYSA-N 1,3-dimethoxypropan-2-ol Chemical compound COCC(O)COC ZESKRVSPQJVIMH-UHFFFAOYSA-N 0.000 claims description 2
- PZYHLENTJZMOQC-UHFFFAOYSA-N 1-bromohexan-1-ol Chemical compound CCCCCC(O)Br PZYHLENTJZMOQC-UHFFFAOYSA-N 0.000 claims description 2
- WHYBHJWYBIXOPS-UHFFFAOYSA-N 1-phenylbutane-2,3-diol Chemical compound CC(O)C(O)CC1=CC=CC=C1 WHYBHJWYBIXOPS-UHFFFAOYSA-N 0.000 claims description 2
- LGZMUUBPTDRQQM-UHFFFAOYSA-N 10-Bromo-1-decanol Chemical compound OCCCCCCCCCCBr LGZMUUBPTDRQQM-UHFFFAOYSA-N 0.000 claims description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 2
- GOSQZSJMSMTIFI-UHFFFAOYSA-N 16-bromohexadecan-1-ol Chemical compound OCCCCCCCCCCCCCCCCBr GOSQZSJMSMTIFI-UHFFFAOYSA-N 0.000 claims description 2
- CCLNWKPQPZBSEI-UHFFFAOYSA-N 2,3-diethoxypropan-1-ol Chemical compound CCOCC(CO)OCC CCLNWKPQPZBSEI-UHFFFAOYSA-N 0.000 claims description 2
- RXDAPJJFRLSRPX-UHFFFAOYSA-N 2,3-dimethoxypropan-1-ol Chemical compound COCC(CO)OC RXDAPJJFRLSRPX-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 claims description 2
- 239000004386 Erythritol Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 2
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 229940061641 androsterone Drugs 0.000 claims description 2
- QGXBDMJGAMFCBF-HLUDHZFRSA-N androsterone group Chemical group [C@@H]12CCC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC[C@H]2C[C@H](O)CC[C@]12C QGXBDMJGAMFCBF-HLUDHZFRSA-N 0.000 claims description 2
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 claims description 2
- 230000001588 bifunctional effect Effects 0.000 claims description 2
- 235000021466 carotenoid Nutrition 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 claims description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 2
- 235000019414 erythritol Nutrition 0.000 claims description 2
- 229940009714 erythritol Drugs 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 229960003471 retinol Drugs 0.000 claims description 2
- 235000020944 retinol Nutrition 0.000 claims description 2
- 239000011607 retinol Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical compound OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 claims description 2
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- 150000002314 glycerols Chemical class 0.000 claims 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 2
- LSFVZANDNULFDT-UHFFFAOYSA-N (1-hydroxy-3-phenylmethoxypropan-2-yl) hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(CO)COCC1=CC=CC=C1 LSFVZANDNULFDT-UHFFFAOYSA-N 0.000 claims 1
- UXSCXYHMONUYDU-UHFFFAOYSA-N (1-hydroxy-3-phenylmethoxypropan-2-yl) icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(CO)COCC1=CC=CC=C1 UXSCXYHMONUYDU-UHFFFAOYSA-N 0.000 claims 1
- MPPODKLDCLFLKT-UHFFFAOYSA-N (3-acetyloxy-2-hydroxypropyl) acetate Chemical compound CC(=O)OCC(O)COC(C)=O MPPODKLDCLFLKT-UHFFFAOYSA-N 0.000 claims 1
- IASVKFIUVMSQAL-UHFFFAOYSA-N (3-hydroxy-2-phenylmethoxypropyl) dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(CO)OCC1=CC=CC=C1 IASVKFIUVMSQAL-UHFFFAOYSA-N 0.000 claims 1
- DNZCZBXYUBLXJD-UHFFFAOYSA-N (3-hydroxy-2-phenylmethoxypropyl) hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(CO)OCC1=CC=CC=C1 DNZCZBXYUBLXJD-UHFFFAOYSA-N 0.000 claims 1
- UCKPWEXXNLWEFT-UHFFFAOYSA-N (3-hydroxy-2-phenylmethoxypropyl) icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)OCC1=CC=CC=C1 UCKPWEXXNLWEFT-UHFFFAOYSA-N 0.000 claims 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 1
- RTMHETZUWPSOMK-UHFFFAOYSA-N 1,3-ditrityloxypropan-2-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)OCC(O)COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 RTMHETZUWPSOMK-UHFFFAOYSA-N 0.000 claims 1
- BHHZLIMTTYVLDT-UHFFFAOYSA-N 1-(oxan-2-yl)hexane-1,6-diol Chemical compound OCCCCCC(O)C1CCCCO1 BHHZLIMTTYVLDT-UHFFFAOYSA-N 0.000 claims 1
- UXVUXXKKXGNKEA-UHFFFAOYSA-N 1-(oxan-2-yl)propane-1,3-diol Chemical compound OCCC(O)C1CCCCO1 UXVUXXKKXGNKEA-UHFFFAOYSA-N 0.000 claims 1
- CUZKCNWZBXLAJX-UHFFFAOYSA-N 2-phenylmethoxyethanol Chemical compound OCCOCC1=CC=CC=C1 CUZKCNWZBXLAJX-UHFFFAOYSA-N 0.000 claims 1
- DCDISHARGWMOMM-UHFFFAOYSA-N 4-phenylbutane-1,3-diol Chemical compound OCCC(O)CC1=CC=CC=C1 DCDISHARGWMOMM-UHFFFAOYSA-N 0.000 claims 1
- YVSCORBGXMFZGV-UHFFFAOYSA-N 7-phenylheptane-1,6-diol Chemical compound OCCCCCC(O)CC1=CC=CC=C1 YVSCORBGXMFZGV-UHFFFAOYSA-N 0.000 claims 1
- ACIAHEMYLLBZOI-ZZXKWVIFSA-N Unsaturated alcohol Chemical compound CC\C(CO)=C/C ACIAHEMYLLBZOI-ZZXKWVIFSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000005011 alkyl ether group Chemical group 0.000 claims 1
- 150000001747 carotenoids Chemical class 0.000 claims 1
- ALSTYHKOOCGGFT-UHFFFAOYSA-N cis-oleyl alcohol Natural products CCCCCCCCC=CCCCCCCCCO ALSTYHKOOCGGFT-UHFFFAOYSA-N 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 150000004665 fatty acids Chemical class 0.000 claims 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims 1
- 229960004063 propylene glycol Drugs 0.000 claims 1
- 235000013772 propylene glycol Nutrition 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- 150000003505 terpenes Chemical class 0.000 claims 1
- 229940067631 phospholipid Drugs 0.000 abstract description 46
- 239000003094 microcapsule Substances 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000000178 monomer Substances 0.000 description 9
- 238000006116 polymerization reaction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229960005150 glycerol Drugs 0.000 description 6
- 229940063557 methacrylate Drugs 0.000 description 6
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 229940035437 1,3-propanediol Drugs 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 4
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 4
- 238000007720 emulsion polymerization reaction Methods 0.000 description 4
- 229940031098 ethanolamine Drugs 0.000 description 4
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229950004354 phosphorylcholine Drugs 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000004952 Polyamide Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000007334 copolymerization reaction Methods 0.000 description 3
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 229920002647 polyamide Polymers 0.000 description 3
- 230000001960 triggered effect Effects 0.000 description 3
- 229910001868 water Inorganic materials 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- GJBXIPOYHVMPQJ-UHFFFAOYSA-N hexadecane-1,16-diol Chemical compound OCCCCCCCCCCCCCCCCO GJBXIPOYHVMPQJ-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000003100 immobilizing effect Effects 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 2
- 235000019394 potassium persulphate Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960002415 trichloroethylene Drugs 0.000 description 2
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- JSPNNZKWADNWHI-PNANGNLXSA-N (2r)-2-hydroxy-n-[(2s,3r,4e,8e)-3-hydroxy-9-methyl-1-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoctadeca-4,8-dien-2-yl]heptadecanamide Chemical compound CCCCCCCCCCCCCCC[C@@H](O)C(=O)N[C@H]([C@H](O)\C=C\CC\C=C(/C)CCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JSPNNZKWADNWHI-PNANGNLXSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical group NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- XFXOYMYVQFERQY-UHFFFAOYSA-N C(CCCCCCCCCCCCCCCCC)P(=O)=C(O)CN Chemical compound C(CCCCCCCCCCCCCCCCC)P(=O)=C(O)CN XFXOYMYVQFERQY-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010056740 Genital discharge Diseases 0.000 description 1
- UXDDRFCJKNROTO-UHFFFAOYSA-N Glycerol 1,2-diacetate Chemical compound CC(=O)OCC(CO)OC(C)=O UXDDRFCJKNROTO-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010021703 Indifference Diseases 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical class C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- 229940117913 acrylamide Drugs 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate group Chemical group C(C=C)(=O)[O-] NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical group C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229930183167 cerebroside Natural products 0.000 description 1
- RIZIAUKTHDLMQX-UHFFFAOYSA-N cerebroside D Natural products CCCCCCCCCCCCCCCCC(O)C(=O)NC(C(O)C=CCCC=C(C)CCCCCCCCC)COC1OC(CO)C(O)C(O)C1O RIZIAUKTHDLMQX-UHFFFAOYSA-N 0.000 description 1
- 125000003901 ceryl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([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 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000000332 continued effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical compound FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 125000005641 methacryl group Chemical group 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000000913 palmityl 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])C([H])([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 1
- 150000002978 peroxides Chemical class 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000000075 primary alcohol group Chemical group 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000003198 secondary alcohol group Chemical group 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F30/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F30/02—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing phosphorus
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Polymers & Plastics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Medicinal Preparation (AREA)
Abstract
Abstract of the Disclosure Polymerizable phospholipids of the general formula I
(CH2 = ? - ? -)n - A I
in which n denotes an integer with a value from 1 to 6, R1 denotes a hydrogen atom or a methyl group and A denotes the radical, bonded via the polar or apolar region of the molecule, of a, phospholipid or phospholipid analogue of the general formula II
in which R represents the lipophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospho-lipid molecule, and a process for their preparation are described.
(CH2 = ? - ? -)n - A I
in which n denotes an integer with a value from 1 to 6, R1 denotes a hydrogen atom or a methyl group and A denotes the radical, bonded via the polar or apolar region of the molecule, of a, phospholipid or phospholipid analogue of the general formula II
in which R represents the lipophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospho-lipid molecule, and a process for their preparation are described.
Description
I ~ 6783~
The invention relates to polymerizable phospho-lipids and a process for their preparation1 and polymeric phospholipids which can be formed from these polymer-izable phospholipids, a process for tneir preparat.on and their use for the production of microcapsules.
It is already known that a large number of nat-urally occurring or synthetic materials can be used ~or the fcrmation of micro^apsules which can be used for en-capsulating an~ stabilizin~ med.cinal active cvmpounds or other active substances, such as enzymes, and for pro-te~ting these compounds unti] they are llsed ir. the inten-ded manner.
The m.aterials traditionally used for forming microcapsules are, for example, synthetic polymers, such as polyamides, or naturally occurring materiaJ~, such a_ gelatin. - However, these materials can~ot be comple~el~
satisfactory, since in some cases they necessitate multi-co~nponent systems, using organic solv~r~ts, for the for-~ mation of the microcapsules, do not have the required stability, cannot be biologically degraded or may display harmful side effects when they are to be employed for encapsulating medicinal active compounds.
The object of the present invention is thus to ~5 provide a material which is considerably more suitable for encapsulating active substances or otherwise immobil-izing them than the materials traditionally employed.
It has now been found, surprisingly, that poly-meric phospholipids which, because of their lipid charac-~`
.
" ~ : :
. ~
~ 1 ~7~,3~3 ter, are capable of forming spontaneously organized structures (vesicles, artificial liposomes) about U.05 to 100 um in size in an aqueous medium, can be formed from polymerizable phospholipids These particles are hollow spheres and are thus suitable for microencapsulat-ing water-soluble medicinal active compounds or other active compounds Furthermore, lipophilic substances can be concentrated in such microcapsules if, like chol-esterol, for example, they are soluble in the hydrophobic part of the polymers.
In particular, the invention relates to the poly-rnerizable phospholipids of the Eollowing general Eorrnula Rl O
,.
~CH2 = C - C -) - A (I) in which n denotes an integer with a value from 1 to 6, R denotes a hydrogen atoln or a methyl group and A de-notes the radical, bonded via the polar or apolar region of the molecule, of a phospholipid or phospholipid ana-logue of the general formula II
R - PO4H - Z (II) .. -. .
.
- "` 1 1 67~3~
in which R represents the lipophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospholipid molecule The radical ~ in the above general formula I pre-ferably represents the radical of a phospholipid which is isolated from naturally occurring material, such as egg yol~, soya bean or the like and which contains functional groups fr-om which derivatives can be formed, such as hydroxyl groups or amino groups, such as, for example, a cephalin, phosphatidylserine, phosphatidylglycerol, phos-phatidylinositol, cardiolipin, sphingomyelin or cerebro-side radieal or respeetive synthetie phospholipids of natural structure Aceording to a preferred embodiment of the inven-tion, the polymerizable phospholipids correspond to the following general formula III
O
R - P04H - Z - (- C - C = CH~)n . (III) in whieh n denotes an integer with a value from 1 to 6, Rl denotes a hydrogen atom or a methyl group and the radical R represents a radical seleeted from groups A) to K) defined below:
Group A comprises radieals of monohydrie alcohols, such as hexanol, decanol, hexadecanol, eicosanol and hexacosanol, and of cyclohexanol and corresponding com-'' - .
7~338 pounds which are halogenated, such as, for example, bromo-l-hexanol, 10-bromo-1-decanol and 16-bromo-1-hexadecanol, or unsaturated, such as g-octadecan-l-ol.
Group B comprises radicals of compounds which are formed by monosubstitution o~ allcanediols, with etherification or esterificatin, such as acetylglycol, ethylglycol, decanoylglycol, decylglycol, hexadecanoyl-glycol, hexadecylglycol~ eicosanoylglycol and eisosyl-glycol, and corresponding monoacyl or monoalkyl deriva-tives of 1,3-propanediol, ].,2-propanediol, 1,6-hexane-diol/ l,lU-decanediol and 1,16-hexadecanediol, which, like the glycol derivatives, can easily be prepared in a Known manner.
Group C comprises radicals of compounds which have likewise been built up from alicanediols but which contain ether groupings which are unstable to acid, such as, for example, the trityl or tetrahydropyranyl radical, such as l-tritylglycol, l-tetrahydropyranyl-glycol, l-trityl-1,3-propanediol, l-tetrahydropyranyl-1,6-hexanediol, l-trityl-l,10-decanediol, l-tetrahydro-pyranyl-l,10-decanediol, 1-trityl-1,16-hexadecanediol and l-tetrahydropyranyl-1~16-hexadecanediol. These compounds can also easily be prepared in a Icnown manner.
1 1 6~P)38 Group D likewise comprises radicals of com-pounds which are built up from alkanediols, but which contain either groups which can be removed again by cata-lytic hydrogenolysis, for exarnple benzyl ethers, such as l-benzylglycol, l-benzyl-1,3-propanediol, 1-benzyl-1,2-propanediol, l-benzyl-1,6-hexanediol, l-benzyl-l,10-dec-anediol and l-benzyl-1,16-hexadecanediol. These com-pounds can also easil~7 be prepared in a known manner.
Group E comprises radicals of compounds which are built up on the fur.dame~ltal glycerol skeleton and in which two alcohol groups are substituted as in the case of the radicals of group B, such as radicals oE
1,2-dimethylglycerol, 1,3-dimethylglycerol, 1,2-diacetyl-glycerol, l/3-diacetylglycerol, 1,2-diethylglycerol and 1,3-diethylglycerol and of corresponding esters with higher fatty acid radicals, such as capric acid, lauric acid, palmitic acid, arachic acid, oleic acid and lino-leic acid, or of ethers with higher alkyl radicals, such as decyl, hexadecyl and hexacosyl, and of mixed ester compounds, ether compounds or ester/ether compounds.
The corresponding starting materials can be prepared by known processes.
Group F comprises radicals of glycerol deriva-tives which contain groups which are unstable to acid, such as ditrityl radicals, such asl for example, 1,3-.:
'' ' ' ~ ~ ..
--6--ditritylglycerol or 1,2-isopropylideneglycerol.
Group G comprises radicals of compounds which are built up from glycerol but which, as in the case of the radicals of Group D, contain ether groupings which car be removed again by catalytic hydrogenolysis, for ex-ample benzyl ethers, such as l-benzyl-2-lauroyl-glycerol, l-lauroyl-2-benzyl-glycerol, 1-benzyl-2-palmitoyl-gly-cerol, l-palmitoyl-~-benzoyl-glycerol, 1-benzyl-2-arach-oyl-glycerol and l-arachoyl-2-benzyl-glycerol, and the corresponding alkyl ethers.
Group H comprises radicals of compounds of the type from which the radicals of groups B and E are der-ived, but with polyalcohols as the fundamental skeleton.
A n-polyol always contains n-l substituents and a free hydroxyl group, which can then be reacted by known pro-cesses to give the phosphoric acid diester (R-P04H-Z).
Examples of suitable polyols are erythritol, arabitol, xylitol, adonitol, mannitol, sorbitol and dulcitol.
Group I comprises radicals of compounds of the type from which the radicals Qf groups G and F are der-ived, these radicals being based on polyalcohols which are again unstable to acid. In a n-polyol, n-1 groups are protected, that is to say one free primary or secon-dary alcohol group is present, which again is available for reaction to give the phosphoric acid diester.
~ .
I 1 67~38 Group J comprises radicals of compounds of the type fran which the radicals of groups D and G are der-ived, these radicals con~aining ether groupings which can be removed again by catalytic hydrogenolysis.
Group K comprises the radicals of other biologi-cally and pharmaceutically interesting li~ophilic alco-hols which contain a primary or secondary hydroxyl group, such as, for example, of cholesterol, retinol, andro-sterone, ergosterol and other steroid alcohols, isopre-noid alcohols and carotenoid alcohols.
Group Z in the above general formula III repres-ents the polar portion of the molecule, which is bonded to the radical R via the phosphate group, and corres-ponds to one of the formulae 1) to 6) given below, the hetero-atom (O or N) on the right-hand side of the group-ing representing the bonding member to the polymerizable radical (acrylic acid radical or methacrylic acid radi-cal).
1) (CH2)a NH wherein a has a value from 2 to 10,
The invention relates to polymerizable phospho-lipids and a process for their preparation1 and polymeric phospholipids which can be formed from these polymer-izable phospholipids, a process for tneir preparat.on and their use for the production of microcapsules.
It is already known that a large number of nat-urally occurring or synthetic materials can be used ~or the fcrmation of micro^apsules which can be used for en-capsulating an~ stabilizin~ med.cinal active cvmpounds or other active substances, such as enzymes, and for pro-te~ting these compounds unti] they are llsed ir. the inten-ded manner.
The m.aterials traditionally used for forming microcapsules are, for example, synthetic polymers, such as polyamides, or naturally occurring materiaJ~, such a_ gelatin. - However, these materials can~ot be comple~el~
satisfactory, since in some cases they necessitate multi-co~nponent systems, using organic solv~r~ts, for the for-~ mation of the microcapsules, do not have the required stability, cannot be biologically degraded or may display harmful side effects when they are to be employed for encapsulating medicinal active compounds.
The object of the present invention is thus to ~5 provide a material which is considerably more suitable for encapsulating active substances or otherwise immobil-izing them than the materials traditionally employed.
It has now been found, surprisingly, that poly-meric phospholipids which, because of their lipid charac-~`
.
" ~ : :
. ~
~ 1 ~7~,3~3 ter, are capable of forming spontaneously organized structures (vesicles, artificial liposomes) about U.05 to 100 um in size in an aqueous medium, can be formed from polymerizable phospholipids These particles are hollow spheres and are thus suitable for microencapsulat-ing water-soluble medicinal active compounds or other active compounds Furthermore, lipophilic substances can be concentrated in such microcapsules if, like chol-esterol, for example, they are soluble in the hydrophobic part of the polymers.
In particular, the invention relates to the poly-rnerizable phospholipids of the Eollowing general Eorrnula Rl O
,.
~CH2 = C - C -) - A (I) in which n denotes an integer with a value from 1 to 6, R denotes a hydrogen atoln or a methyl group and A de-notes the radical, bonded via the polar or apolar region of the molecule, of a phospholipid or phospholipid ana-logue of the general formula II
R - PO4H - Z (II) .. -. .
.
- "` 1 1 67~3~
in which R represents the lipophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospholipid molecule The radical ~ in the above general formula I pre-ferably represents the radical of a phospholipid which is isolated from naturally occurring material, such as egg yol~, soya bean or the like and which contains functional groups fr-om which derivatives can be formed, such as hydroxyl groups or amino groups, such as, for example, a cephalin, phosphatidylserine, phosphatidylglycerol, phos-phatidylinositol, cardiolipin, sphingomyelin or cerebro-side radieal or respeetive synthetie phospholipids of natural structure Aceording to a preferred embodiment of the inven-tion, the polymerizable phospholipids correspond to the following general formula III
O
R - P04H - Z - (- C - C = CH~)n . (III) in whieh n denotes an integer with a value from 1 to 6, Rl denotes a hydrogen atom or a methyl group and the radical R represents a radical seleeted from groups A) to K) defined below:
Group A comprises radieals of monohydrie alcohols, such as hexanol, decanol, hexadecanol, eicosanol and hexacosanol, and of cyclohexanol and corresponding com-'' - .
7~338 pounds which are halogenated, such as, for example, bromo-l-hexanol, 10-bromo-1-decanol and 16-bromo-1-hexadecanol, or unsaturated, such as g-octadecan-l-ol.
Group B comprises radicals of compounds which are formed by monosubstitution o~ allcanediols, with etherification or esterificatin, such as acetylglycol, ethylglycol, decanoylglycol, decylglycol, hexadecanoyl-glycol, hexadecylglycol~ eicosanoylglycol and eisosyl-glycol, and corresponding monoacyl or monoalkyl deriva-tives of 1,3-propanediol, ].,2-propanediol, 1,6-hexane-diol/ l,lU-decanediol and 1,16-hexadecanediol, which, like the glycol derivatives, can easily be prepared in a Known manner.
Group C comprises radicals of compounds which have likewise been built up from alicanediols but which contain ether groupings which are unstable to acid, such as, for example, the trityl or tetrahydropyranyl radical, such as l-tritylglycol, l-tetrahydropyranyl-glycol, l-trityl-1,3-propanediol, l-tetrahydropyranyl-1,6-hexanediol, l-trityl-l,10-decanediol, l-tetrahydro-pyranyl-l,10-decanediol, 1-trityl-1,16-hexadecanediol and l-tetrahydropyranyl-1~16-hexadecanediol. These compounds can also easily be prepared in a Icnown manner.
1 1 6~P)38 Group D likewise comprises radicals of com-pounds which are built up from alkanediols, but which contain either groups which can be removed again by cata-lytic hydrogenolysis, for exarnple benzyl ethers, such as l-benzylglycol, l-benzyl-1,3-propanediol, 1-benzyl-1,2-propanediol, l-benzyl-1,6-hexanediol, l-benzyl-l,10-dec-anediol and l-benzyl-1,16-hexadecanediol. These com-pounds can also easil~7 be prepared in a known manner.
Group E comprises radicals of compounds which are built up on the fur.dame~ltal glycerol skeleton and in which two alcohol groups are substituted as in the case of the radicals of group B, such as radicals oE
1,2-dimethylglycerol, 1,3-dimethylglycerol, 1,2-diacetyl-glycerol, l/3-diacetylglycerol, 1,2-diethylglycerol and 1,3-diethylglycerol and of corresponding esters with higher fatty acid radicals, such as capric acid, lauric acid, palmitic acid, arachic acid, oleic acid and lino-leic acid, or of ethers with higher alkyl radicals, such as decyl, hexadecyl and hexacosyl, and of mixed ester compounds, ether compounds or ester/ether compounds.
The corresponding starting materials can be prepared by known processes.
Group F comprises radicals of glycerol deriva-tives which contain groups which are unstable to acid, such as ditrityl radicals, such asl for example, 1,3-.:
'' ' ' ~ ~ ..
--6--ditritylglycerol or 1,2-isopropylideneglycerol.
Group G comprises radicals of compounds which are built up from glycerol but which, as in the case of the radicals of Group D, contain ether groupings which car be removed again by catalytic hydrogenolysis, for ex-ample benzyl ethers, such as l-benzyl-2-lauroyl-glycerol, l-lauroyl-2-benzyl-glycerol, 1-benzyl-2-palmitoyl-gly-cerol, l-palmitoyl-~-benzoyl-glycerol, 1-benzyl-2-arach-oyl-glycerol and l-arachoyl-2-benzyl-glycerol, and the corresponding alkyl ethers.
Group H comprises radicals of compounds of the type from which the radicals of groups B and E are der-ived, but with polyalcohols as the fundamental skeleton.
A n-polyol always contains n-l substituents and a free hydroxyl group, which can then be reacted by known pro-cesses to give the phosphoric acid diester (R-P04H-Z).
Examples of suitable polyols are erythritol, arabitol, xylitol, adonitol, mannitol, sorbitol and dulcitol.
Group I comprises radicals of compounds of the type from which the radicals Qf groups G and F are der-ived, these radicals being based on polyalcohols which are again unstable to acid. In a n-polyol, n-1 groups are protected, that is to say one free primary or secon-dary alcohol group is present, which again is available for reaction to give the phosphoric acid diester.
~ .
I 1 67~38 Group J comprises radicals of compounds of the type fran which the radicals of groups D and G are der-ived, these radicals con~aining ether groupings which can be removed again by catalytic hydrogenolysis.
Group K comprises the radicals of other biologi-cally and pharmaceutically interesting li~ophilic alco-hols which contain a primary or secondary hydroxyl group, such as, for example, of cholesterol, retinol, andro-sterone, ergosterol and other steroid alcohols, isopre-noid alcohols and carotenoid alcohols.
Group Z in the above general formula III repres-ents the polar portion of the molecule, which is bonded to the radical R via the phosphate group, and corres-ponds to one of the formulae 1) to 6) given below, the hetero-atom (O or N) on the right-hand side of the group-ing representing the bonding member to the polymerizable radical (acrylic acid radical or methacrylic acid radi-cal).
1) (CH2)a NH wherein a has a value from 2 to 10,
2) -(CH2)b-- wherein b has a value from 2 to 10,
3) -(CH2)-(CHOH)c-CH2-o- wherein c has a value from 1 to
4) -(CH2)x-l~+-(CH2)y~0~ wherein x and y independently CH3 of one another can assume val-ues from 2 to 10, '.
~ . .
~ J ~7~3~
~ . .
~ J ~7~3~
5 ) -CH2-C-i~H
COOH
or CH3
COOH
or CH3
6) -(CH2)X-l~+-(CH~)y~i~H~ wherein x and y independently CH3 of one another can assume val-ues from 2 to 10.
However, it is also possible for several hydroxyl groups or amino groups in the molecular radical Z to be linked to the polymerizable radical. Crosslinked poly-mers, which can be used as filter materials, for ex-ample as tobacco filters, can.thereby be formed.
According to another embodiment of the inven~on, the polymerizable phospholipids correspond to the follow-ing general formula IV
Rl O
~, (CH2 = C - C ~ )n ~ R - PO4H - Z (IV) wherein, ln this case, the polymerizable group is bonded in the apolar region of the r.lolecule. In this general formula IV, the symbols Rl and n have the abovementioned meanings, whilst ~
A) represents an alkyl radical which is at least bifunc-tional and has 6 to 22, preferably 12 to 22, carbon atoms, such as, for example, an alkanediol, amino alcohol or alkanediamine radical;
b) represents the radical of a monosubstituted alkane-, ~ 1 67~33~
diol, amino alcohol or al~anediamine which has 2 to 6carbon atoms, which carry a substituent which has 6 to 22, preferably 12 to 22, carbon atoms and an ester, ether or amide lin~age, and which contains at least one additional amino or alcohol group;
C) represents the radical of a monosubstituted or di-substituted ylycerol derivative which carries substitu-ents as mentioned under ~); or ~) re~resents the radical of a monosubstituted or poly-substituted (nOH-l) polyol which carries substituents as mentioned under B), and Z represents a group of one of the following general formulae 1) to 10) or a hydrogen atom:
1) (CH2)a NH2 wherein a has a value from 2 to 10, 2) -(CH2)b-OH wherein b has a value from 2 to 1~, 3) -(CH2)-(CHOH)c-CH2-OH wherein c has a value from 1 ,CH3 to 4, 4) ~(CH2)X~N~~(CH2)y~OH wherein x and y independently CH3 of one another can assume val-H ues from 2 to 10, 5) -CH2-C-I~H2 COOH
~,~, .~
I ~ ~7~,3~
6) -(CH2)X-N~-(cH2)y NH2 wherein x and y independently CH3 of one another can assume val-ues from 2 to 10, +
However, it is also possible for several hydroxyl groups or amino groups in the molecular radical Z to be linked to the polymerizable radical. Crosslinked poly-mers, which can be used as filter materials, for ex-ample as tobacco filters, can.thereby be formed.
According to another embodiment of the inven~on, the polymerizable phospholipids correspond to the follow-ing general formula IV
Rl O
~, (CH2 = C - C ~ )n ~ R - PO4H - Z (IV) wherein, ln this case, the polymerizable group is bonded in the apolar region of the r.lolecule. In this general formula IV, the symbols Rl and n have the abovementioned meanings, whilst ~
A) represents an alkyl radical which is at least bifunc-tional and has 6 to 22, preferably 12 to 22, carbon atoms, such as, for example, an alkanediol, amino alcohol or alkanediamine radical;
b) represents the radical of a monosubstituted alkane-, ~ 1 67~33~
diol, amino alcohol or al~anediamine which has 2 to 6carbon atoms, which carry a substituent which has 6 to 22, preferably 12 to 22, carbon atoms and an ester, ether or amide lin~age, and which contains at least one additional amino or alcohol group;
C) represents the radical of a monosubstituted or di-substituted ylycerol derivative which carries substitu-ents as mentioned under ~); or ~) re~resents the radical of a monosubstituted or poly-substituted (nOH-l) polyol which carries substituents as mentioned under B), and Z represents a group of one of the following general formulae 1) to 10) or a hydrogen atom:
1) (CH2)a NH2 wherein a has a value from 2 to 10, 2) -(CH2)b-OH wherein b has a value from 2 to 1~, 3) -(CH2)-(CHOH)c-CH2-OH wherein c has a value from 1 ,CH3 to 4, 4) ~(CH2)X~N~~(CH2)y~OH wherein x and y independently CH3 of one another can assume val-H ues from 2 to 10, 5) -CH2-C-I~H2 COOH
~,~, .~
I ~ ~7~,3~
6) -(CH2)X-N~-(cH2)y NH2 wherein x and y independently CH3 of one another can assume val-ues from 2 to 10, +
7) -(CH2)d-NCH3~2 wherein d denotes an integer from 2 to 10~
8) -(CH )3-N(CH3)2H wherein e denotes an integer from 2 to 10, g) (cH2)f N( 3)3 whereir.-f denotes an integer . from 2 to 10, or 10) ~CH2)g~H wherein g denotes an integer from 2 to 10.
The polymerizable phospholipids aecordiny to the invention can be prepared by introdueing the polymer-izable acrylie aeid or methaerylie acid radieals into the phospholipid or the phospholipid analogue via the partieular aeid ehloride or with the aid of the custom-ary condensation methods, with the formation of the corresponding ~onomeric estes or amides.
This procedure eomprises subjeeting a reaeting acrylic aeid derivative of the following general formula R O
CH2 = C - C - X (V) t 1 ~7~338 in which X represents a halogen atom, a hydroxyl group or another easily replaceable molecular group and Rl re-presents a hydrogen atom or a methyl group, to a conden-sation reaction with a phospholipid of the followi.ng gen-eral formula II
R P04H X ~II) in which R and Z have the abovementioned meanings, in a manner which is known per se.
The condensation reactlon can be carried out in a manner such that the polymerizable functional group is located either in the polar region or in the apolar region of the molecule of the phospholipid or of the phospholipid analogue, resulting in cornpounds of the general formulae III and IV described above.
The polmerizable phospholipids according to the invention can be polymerized by homopolymerization or by copolymerization, with the aid of customary polymeriza-tion inhibitors, such as a,a' azobisisobutyronl;trile, di-benzoyl peroxide, ri.boflavin, a peroxydisulfate and the li~e, to give polyrneric phospholipids of the following general formula VI
- -(R )m ~ (CH2-c )n tR )p - (CH2-C ~ (R )q - (VI) C=O C=O
A A -~ .
I 1 67~338 to which the invention likewise relates. In the above general formula VI, n, Rl and A have the abovementioned meanings, whilst R2 represents the radical of an identi-cal or different copolymerizable monomer and m, p and q independently of one another denote integers with values from U to 6. The radical R2 preferably represents the radical of a copolymerizable acrylor vinyl compound, such as acryIic acid, methacrylic acid, al~yl acrylates or methacrylates with in each case 1 to 22 carbon atoms in the alkyl group, vinyl chloride, vinyl fluoride, vinyl bromide or vinyl esters or vinyl ethers with in each case 1 to 22 carbon atoms in the al~yl group. The degree of polymerization of these polymeric phospholip-ids according to the invention is greater than 10, which corresponds to a lower limit for a molecular weight of about 8,000.
The homopol-ylnerization or copolymerization of the polymerizable phospnolipids according to the inven-tion, with formation or the polymeric phospholipids of the general formula VI described above, can be carried out a) in the absence of solvents (in bul~), b) in homo-geneous solution (solution polymerization) or c) in aqueous emulsion (emulsion polymerization), with the aid of the polymelization initiators described above, and using customary procedures. ~loc~ copolymerization is preferably effected.
I ~ ~783~
~ ecause of their lipid character, the polymeric phospholipids, according to the lnvention, of the gen-eral formula VI described above are capable of forming spontaneously organized structures (vesicles or arti-ficial liposomes) about ~.-05 to 10~ um in size in an aqueous medium. These particles are hollow spheres and are therefore suitable for microencapsulating water-soluble pharmaceutical active compounds or other active compounds Lipophilic substances can lilcewise be con-centrated in such microcapsules if, like cholesterol, for example, they are solubl'e in the hydrophobic part of the polymer.
The inventio~ thus also relates to the use of polymeric phospholipids of the general formula I des-cribed above for the preparation of microcapsules.
From the method point of view, microencapsulat-ion is achieved by polymerization of the polymerizable phospholip.ids of..'che general formula I or III and IV
according to the invention in the presence of the sub-stance to be encapsulated. Methods such as dialysis, centrifugation and column chromatography have proved suitable for purification and isolation of the.loaded microcapsules, ,~ ., ,"~, " :
- .
;: :
I 1 6~33~3 The advantage of the microcapsules of the poly-meric phospholipid of the present invention, which are formed using the polymerizable phospholipids according to the invention, compared with aetificial liposomes of simple lipids is the higher stability of the polymeric phospholipids according to the invention.
The advantage compared with microcapsules of traditional polymeric materials, such as polyamides, lies 1) in the milder method of encapsulation, which takes place in an aqueous medium, so that no two-compollent system with an organic solvent is necessary, and 2) in the fact that the polymeric phospholipids accord-in~ to the invention are very similar to the naturally occurring membrane components, that is to say substan-tial biological degradability is ensured and immunolog-ical indifference is to be expected.
Since the boundary conditions (temperature of less than 60C aqueous rnediurn) can be very gentle, en-capsulation of very sensitive substances, such as en-zymes, is also possible according to the invention.
This results in the possibility of immobilizing enzymes without these having ~o be fixed via covalent bonding.
I 1 67~38 The polymeric phospholipids according to the in-vention are an immobilized lipid matrix and can there-rore be used as adsorbents for lipophilic compounds, for example as a base material for affinity chromatograp.hy or as a stabilizer for lipophilic proteins.
The polymeric phospholipids accordng to the in-vention can also be formed by polymerization in the pre-sence of customary crosslin~ing agents, crosslinked poly-mers being obtained. It is also possible for polymer-iæable phospholipids which have the abovementioned gen-eral formula I ana contain two unsaturated groups suit-able for polymerixation to be employed as crosslinicing agents.
rrhe following examples serve to illustrate the invention further.
Examples 1 to 9 relate to the synthesis of poly-merizable~phospholipids which contain one or more poly-merizable functional groups in the polar molecular reg-ionr Examples 10 to 12 relate to the synthesis of poly-merizable phospholipids which contain one or more poly-merizable functional groups in the apolar mQlecular reg-ion, Examples 13 to 18 relate to the preparation of the polymeric phospholipids according to the invention and Example 19 relates to their use for the preparation of microcapsules.
::
~ 338 Example 1 The polymerizable phospholipids containing acryl-amide groups are obtained by applying the procedure given below.
N-~ethacrylamido-(1,2-dimyristoyl-rac-glycerol-3-phospho-r l)-ethanolamine Y
2 g (2 x 10 2 moles~ of triethylamine are added to 5.4 g (10 2 mole) of 1,2-dimyristoyl-rac-glycerol-3-phosphoryl-ethanolamine in 100 ml of trichloroethylene.
A solution of 2.1 g (1.5 x 10 2 moles) of methacryl chloride in 50 ml of chloroform is added dropwise, whilst cooling with ice and stirring. After the drop-wise addition, stirring of the reaction mixture is con-tinued at room temperature for a further hour; ~there-after the triethylammonium hydrochloride which has pre-cipitated is filtered off and the filtrate is concen-trated to dryness (oil) at 25C in a rotary evaporator.
The residue is treated with 150 ml of saturated aqueous sodium chloride solution and the product is extracted with chloroform. The chloroforrn extract is dried over sodium sulfate and concentrated to 10 ml and the concentrate is discharged onto a silica gel column (Merclc HR 60). Solvent systems CHC13;CH30H;H~O: 1)200:
, .
~ .
15;1; 2) 100:15:1; 3) 65;15:1 (V/V). The purification by column chromatography gives 5.5 g (78~ of theory) of a colorless substance which is still just solid at room temperature.
Example 2 The preparation of the polymerizable phospholip-ids according to the invention which contain acrylate groups is carried out by applying the following proce-dure: ~
Octadecyl-phosphorylqlycerol l!~ono-methacrylate 4.5 g (10 2 mole) of actadecyl-phosphorylglycer-ol are dissolved in 50 ml of trichloroethylenet 2 g (2 x 10 2 moles) of triethylamine are added and the mixture is added dropwise to a solution of 2.1 g (1.5 x 10 2 moles) of methacrylyl chloride ln 50 ml of trichloro-ethylene in the course of 20 minutes, whilst stirring and cooling with ice. After 2 hours, the triethyl-ammonium hydro~chloride formed is filtered off and the filtrate is concentrated to dryness at 30C under a waterpump vacuum in a rotary evaporator. For hydroly-sis, the residue is treated with 200 ml of saturated sodium chloride solution, after which the product is ex-tracted with chloroform. The chloroform phase is dried over sodium sulfate and concentrated , after which the product is purified by column chromatography (silica ~1 , .
'
The polymerizable phospholipids aecordiny to the invention can be prepared by introdueing the polymer-izable acrylie aeid or methaerylie acid radieals into the phospholipid or the phospholipid analogue via the partieular aeid ehloride or with the aid of the custom-ary condensation methods, with the formation of the corresponding ~onomeric estes or amides.
This procedure eomprises subjeeting a reaeting acrylic aeid derivative of the following general formula R O
CH2 = C - C - X (V) t 1 ~7~338 in which X represents a halogen atom, a hydroxyl group or another easily replaceable molecular group and Rl re-presents a hydrogen atom or a methyl group, to a conden-sation reaction with a phospholipid of the followi.ng gen-eral formula II
R P04H X ~II) in which R and Z have the abovementioned meanings, in a manner which is known per se.
The condensation reactlon can be carried out in a manner such that the polymerizable functional group is located either in the polar region or in the apolar region of the molecule of the phospholipid or of the phospholipid analogue, resulting in cornpounds of the general formulae III and IV described above.
The polmerizable phospholipids according to the invention can be polymerized by homopolymerization or by copolymerization, with the aid of customary polymeriza-tion inhibitors, such as a,a' azobisisobutyronl;trile, di-benzoyl peroxide, ri.boflavin, a peroxydisulfate and the li~e, to give polyrneric phospholipids of the following general formula VI
- -(R )m ~ (CH2-c )n tR )p - (CH2-C ~ (R )q - (VI) C=O C=O
A A -~ .
I 1 67~338 to which the invention likewise relates. In the above general formula VI, n, Rl and A have the abovementioned meanings, whilst R2 represents the radical of an identi-cal or different copolymerizable monomer and m, p and q independently of one another denote integers with values from U to 6. The radical R2 preferably represents the radical of a copolymerizable acrylor vinyl compound, such as acryIic acid, methacrylic acid, al~yl acrylates or methacrylates with in each case 1 to 22 carbon atoms in the alkyl group, vinyl chloride, vinyl fluoride, vinyl bromide or vinyl esters or vinyl ethers with in each case 1 to 22 carbon atoms in the al~yl group. The degree of polymerization of these polymeric phospholip-ids according to the invention is greater than 10, which corresponds to a lower limit for a molecular weight of about 8,000.
The homopol-ylnerization or copolymerization of the polymerizable phospnolipids according to the inven-tion, with formation or the polymeric phospholipids of the general formula VI described above, can be carried out a) in the absence of solvents (in bul~), b) in homo-geneous solution (solution polymerization) or c) in aqueous emulsion (emulsion polymerization), with the aid of the polymelization initiators described above, and using customary procedures. ~loc~ copolymerization is preferably effected.
I ~ ~783~
~ ecause of their lipid character, the polymeric phospholipids, according to the lnvention, of the gen-eral formula VI described above are capable of forming spontaneously organized structures (vesicles or arti-ficial liposomes) about ~.-05 to 10~ um in size in an aqueous medium. These particles are hollow spheres and are therefore suitable for microencapsulating water-soluble pharmaceutical active compounds or other active compounds Lipophilic substances can lilcewise be con-centrated in such microcapsules if, like cholesterol, for example, they are solubl'e in the hydrophobic part of the polymer.
The inventio~ thus also relates to the use of polymeric phospholipids of the general formula I des-cribed above for the preparation of microcapsules.
From the method point of view, microencapsulat-ion is achieved by polymerization of the polymerizable phospholip.ids of..'che general formula I or III and IV
according to the invention in the presence of the sub-stance to be encapsulated. Methods such as dialysis, centrifugation and column chromatography have proved suitable for purification and isolation of the.loaded microcapsules, ,~ ., ,"~, " :
- .
;: :
I 1 6~33~3 The advantage of the microcapsules of the poly-meric phospholipid of the present invention, which are formed using the polymerizable phospholipids according to the invention, compared with aetificial liposomes of simple lipids is the higher stability of the polymeric phospholipids according to the invention.
The advantage compared with microcapsules of traditional polymeric materials, such as polyamides, lies 1) in the milder method of encapsulation, which takes place in an aqueous medium, so that no two-compollent system with an organic solvent is necessary, and 2) in the fact that the polymeric phospholipids accord-in~ to the invention are very similar to the naturally occurring membrane components, that is to say substan-tial biological degradability is ensured and immunolog-ical indifference is to be expected.
Since the boundary conditions (temperature of less than 60C aqueous rnediurn) can be very gentle, en-capsulation of very sensitive substances, such as en-zymes, is also possible according to the invention.
This results in the possibility of immobilizing enzymes without these having ~o be fixed via covalent bonding.
I 1 67~38 The polymeric phospholipids according to the in-vention are an immobilized lipid matrix and can there-rore be used as adsorbents for lipophilic compounds, for example as a base material for affinity chromatograp.hy or as a stabilizer for lipophilic proteins.
The polymeric phospholipids accordng to the in-vention can also be formed by polymerization in the pre-sence of customary crosslin~ing agents, crosslinked poly-mers being obtained. It is also possible for polymer-iæable phospholipids which have the abovementioned gen-eral formula I ana contain two unsaturated groups suit-able for polymerixation to be employed as crosslinicing agents.
rrhe following examples serve to illustrate the invention further.
Examples 1 to 9 relate to the synthesis of poly-merizable~phospholipids which contain one or more poly-merizable functional groups in the polar molecular reg-ionr Examples 10 to 12 relate to the synthesis of poly-merizable phospholipids which contain one or more poly-merizable functional groups in the apolar mQlecular reg-ion, Examples 13 to 18 relate to the preparation of the polymeric phospholipids according to the invention and Example 19 relates to their use for the preparation of microcapsules.
::
~ 338 Example 1 The polymerizable phospholipids containing acryl-amide groups are obtained by applying the procedure given below.
N-~ethacrylamido-(1,2-dimyristoyl-rac-glycerol-3-phospho-r l)-ethanolamine Y
2 g (2 x 10 2 moles~ of triethylamine are added to 5.4 g (10 2 mole) of 1,2-dimyristoyl-rac-glycerol-3-phosphoryl-ethanolamine in 100 ml of trichloroethylene.
A solution of 2.1 g (1.5 x 10 2 moles) of methacryl chloride in 50 ml of chloroform is added dropwise, whilst cooling with ice and stirring. After the drop-wise addition, stirring of the reaction mixture is con-tinued at room temperature for a further hour; ~there-after the triethylammonium hydrochloride which has pre-cipitated is filtered off and the filtrate is concen-trated to dryness (oil) at 25C in a rotary evaporator.
The residue is treated with 150 ml of saturated aqueous sodium chloride solution and the product is extracted with chloroform. The chloroforrn extract is dried over sodium sulfate and concentrated to 10 ml and the concentrate is discharged onto a silica gel column (Merclc HR 60). Solvent systems CHC13;CH30H;H~O: 1)200:
, .
~ .
15;1; 2) 100:15:1; 3) 65;15:1 (V/V). The purification by column chromatography gives 5.5 g (78~ of theory) of a colorless substance which is still just solid at room temperature.
Example 2 The preparation of the polymerizable phospholip-ids according to the invention which contain acrylate groups is carried out by applying the following proce-dure: ~
Octadecyl-phosphorylqlycerol l!~ono-methacrylate 4.5 g (10 2 mole) of actadecyl-phosphorylglycer-ol are dissolved in 50 ml of trichloroethylenet 2 g (2 x 10 2 moles) of triethylamine are added and the mixture is added dropwise to a solution of 2.1 g (1.5 x 10 2 moles) of methacrylyl chloride ln 50 ml of trichloro-ethylene in the course of 20 minutes, whilst stirring and cooling with ice. After 2 hours, the triethyl-ammonium hydro~chloride formed is filtered off and the filtrate is concentrated to dryness at 30C under a waterpump vacuum in a rotary evaporator. For hydroly-sis, the residue is treated with 200 ml of saturated sodium chloride solution, after which the product is ex-tracted with chloroform. The chloroform phase is dried over sodium sulfate and concentrated , after which the product is purified by column chromatography (silica ~1 , .
'
9 J ~7~3~
gel Merck HR 60; solvent system CHC13:CH3OH:H2O: 100:
15:1 tV/V). 3.5 g (68% of theory) of a colorless oil which is highly viscous at room temperature are obtained.
Analysis: Octadecyl-phosphorylglycerol mono-methacryl-ate C25H~8~a 7P; MW 514-60 C~ H~ P~
calculated: 58.35 9.40 6.02 found: 58.29 9.30 5.79 Example 3 Octadecyl-phosphoryl-N-methacrylamino-ethanolamine This compound is formed by the procedure of Ex-ample 1, by reacting octadecylphosphorylethanolamine with methacrylyl chloride. The compound is identi-fied by thin layer chromatography.
Er,lpirical formu1a: C24H47NNa O5e; ~W: 483-54 Example 4 1,2-Dipentadecylmethylidene-glycerol-3-phosphoryl-N-acrylamido-ethanolamine The title compound is formed by reacting 1,2-dipentadecylmethylidene-glycerol-3-phosphroyl-ethanol-amine with acrylyl chloride by the procedure in Example 1. .
Empirical formula: C39H75NNaO7P; MS: 723.97 I J 67~33~
C% H~ N% P~
calculated:~4.70 10.44 1.93 4.2~
found: 65.10 10.28 1.89 4.14 Example 5 N-Acrylamido-cephalin The title compound is formed by the procedure of Example 1, by reacting cephalin isolated from eggs with acrylyl chloride. The compound is identified by thin layer chromatography.
Example 6 Octadecylphosphoryl-1,3-propanediol methacrylate The title cornpound is forrned by the procedure of Example 2~ by reacting octadecylphosphoryl-1,3-propane-diol with methacrylyl chloride, Emp rical formula: C25H4~NaO6P; MW; 498.60 C% H% P%
calculated: 60.22 9.70 6.21 found: 58.97 9.4~ 6.02 Example 7 Palmitoyl-1,3-propanediol-phosphoryl-N,N-dimethyl-N-acryloyl)-ethyl~ -ethanolamine The title compound is formed by the procedure of Example 2, and the compound is identified by thin layer chromatography.
1 ~ 67838 --~o--Empirical formula C28H54N8P; i~lW: 563-69 Exarnple 3 1,2-Dimyristolyl-sn-glycerol-3-phosphoryl-1,3-propane-diol methacrylate - The title compound is formed by the procedure of Example 1, by reacting 1,2-diMyristoyl-sn-glycerol-3-phosphoryl-1,3-propanediol with r,lethacrylyl chloride.
The compound is identified by thin layer chromatography.
Empirical formula: C38H70NaO10 ;
Example 9 1,2-Dimyristoyl-sn-glycerol-3-phosphorylglycerol mono-methacrylate The title cornpound is formed by the procedure of Example 2, by reacting 1,2-diMyristoyl-sn-glycerol-3-phosphoryl-glycerol with methacrylyl chloride.
`Empirical formula: C38H70NaOll ;
C% H~ P%
calculated: 60.29 9.32 4.09 found: 59.73 9.22 ~.12 In the following Examples 10 to 12, the polymer-izable radical is introduced into the phospholipid com-pound of the phospholipid analogue by a procedure anala-gous to the procedures given in the above exa~ples, after removal of the protective group (n) by appropriate reactions (hydrogenolysis, acid splitting).
I ~ 6~3~
Example 10 (16-0-Acryloyl)-hexadecanoyl-1,3-propanediol-phosphoryl-choline This compound is formed by reacting 16-hydroxy-hexadecanoyl-1,3-propanediol-phosphorylcholine with acrylyl chloride.
Ernpirical formula: C27Hs2No8o~l~2o; ~ ; 567-69 C%H% N% P%
calculated: 57.129.59 2.47 5.46 found~ 56.92 9.33 - 2.32 S.23 Example 11 1,2-Di-(16-0-acryloyl)-hexadecanoyl-rac-glycerol-3-phos-phorylcholine The title compound is formed by reacting 1,2-di-(16-hydroxy)-hexadecanoyl-rac-glycerol-3-phosphorylchol-ine with acrylyl chloride. The compound is identified by thin layer chrornatography.
Empirical formula: C44H84N012P.H20;
Example 12 (12-l~Jethacryloyl)-octadecanoyl-1,3-propanediol-phosphor-ylcholine The title compound is formed by reacting 12-hydroxystearoyl-1,3-propanediol--phosphorylcholine with methacrylyl chloride. The compound is identified by thin layer chromatography.
.~
~ J 6~38 Empirical formula: C30H58No8o-H2o;
The following Examples 13 to 18 illustrate the preparation of the polymeric phospholipids according to Example 13 B10CK polymerization The general procedure comprises adding 10 to 20 mg (1 to 2% by weight~ of dibenzoy7 peroxide or an equal amount of ~ azoiso~utyronitrile to 1 g of the rnolten monomer (the acryl or methacryl compounds with an alkyl chain are present as highly viscous oils at room ternpera-ture, whilst the compounds with two long-chain alkyl radicals melt in the range between 20 and 50C), whilst stirring. This mixture is then polymerized in a closed reaction vessel under a nitrogen atmosphere at 50 to 60C for 12 to 24 hours. The solid product is comrninuted, and boiled up several times with a chloro-~orm/methanol mixture (1/1, V/V), until no further mono-mer can be detected in the supernatant liquid by thin layer chromatography. The yields are 50 to 95~ of theory, depending on the polymerization temperature and reaction time.
In the abovementioned general procedure, at a polymerization teinperature of 60C and with a polymer-ization time of 30 seconds, using dibenzoyl peroxide as the initiator, poly-(palmitoyl-2,2-dimethyl- 1,3-propane-1 1 67~
diol-phosphorylethanolamino)-methacrylamide is formed in a yield of 87% of theory.
Empirical formula: (C27H51NNaP)p; MW: p. (555 65) C%H~ N% P~
calculated: 5~.25 9.42 2.52 5.56 found: 58.46 8.75 2.20 4.75 Example 14 Solution polymerization Solution polymerization is generally carried out by a procedure in which 1 g of the monomer is dissolved either in 10 ml of dioxane or in 10 ml of ethyl acetete, and 10 mg (1% by weight) of dibenzoyl ~eroxide (or al-ternatively ~,~-azobisisobutyronitrile) are added. The honogeneous solution is then heated to 50C in a closed vessel under a nitrogen atmosphere for 24 hours. The resulting highly viscous solution is then poured into 150 ml of acetone, whereupon the polymeric product is precipitated, and the precipitate is filtered off and dried in a vacuum desiccator. The yields are 70 to 90% of theory.
Poly-(octadecyl-phosphorylglycerol) methacrylate is formed by applying the procedure described above.
Empirical formula: (C25H49O7P);; MW: p. (4~2.64) 1 1 B783~
-2~-C% H% P%
calculated;60.95 10.08b . 25 found: 60,02 9.55 6.23 Example 15 Poly-(1,2-dipalmitoyl-rac-glycerol-3-phosphoryl-1,3-pro~anediol)methacrylate The title compound is formed by the procedure of Example 14.
Empirical formula: ~C42H78NaOl~P) ; ~ p.(797.0) C% H~ P%
calculated: 63.2Y 9.86 3.87 found: 62.57 9.62 3.79 Example 16 Poly-(palmitoyl-2,2-dimethyl-1,3-propanediol-phosphoryl-ethanolaMino)-methacrylamide The title compound is formed by the procedure of Example 14.
Empirical formula: (C27H51NNaO7P)p; MW: p.(555.65) C% H% W% P~
calculated:58.25 9.42 2.52 5,56 found: 57.41 9.06 2.33 4.72 58.88 9.95 4.17 5.61 Example 17 Poly-(1,2-dimyristoyl-sn-glycerol-3-phosphorylethanol-amino)-acrylamide ~`!
..
I J 67~338 The title compound is formed by the procedure of Example 14.
Empirical formula: (C36H67Ni~aO9P~p; ~w p.(712.87) C~ H~ N~ p%
calculated: 60.65 9.62 1.96 4.35 found: 59.99 9.25 2.7S 4.03 Example 18 Emulsion polymerization A) Emulsion polymerization triggered off by heat 5 x 10 4 moles of the monomer are emulsified in 100 ml of aqueous buffer solution (~hosphate buffer with a pH value of 7.0), whilst sha~ing vigorously in a nitrogen atmosphere. 10 to 20 mg of potassium peroxy-disulfate are then added to the emulsion and the flask is flushed again with a vigorous stream of nitrogen and, after being closed, is heated to a temperature of 60C
in a shaking watérbath for 12 to 1~ hours. The pro-gress of the polymerization reaction is followed by thin layer chromatography (solvent system chloroforin/methanol/
25% strength aqueous ammonia (65/15/1)). Chloroform extracts of samples of the aqueous reaction mixture are used for this. The conversion is estimated from the thin layer chromatogram.
~ ~ `
~ 1 67~3fl B) Emulsion polymeri~ation triggered off photochemic-ally 5 x 10 4 moles of the monomer are emulsified in
gel Merck HR 60; solvent system CHC13:CH3OH:H2O: 100:
15:1 tV/V). 3.5 g (68% of theory) of a colorless oil which is highly viscous at room temperature are obtained.
Analysis: Octadecyl-phosphorylglycerol mono-methacryl-ate C25H~8~a 7P; MW 514-60 C~ H~ P~
calculated: 58.35 9.40 6.02 found: 58.29 9.30 5.79 Example 3 Octadecyl-phosphoryl-N-methacrylamino-ethanolamine This compound is formed by the procedure of Ex-ample 1, by reacting octadecylphosphorylethanolamine with methacrylyl chloride. The compound is identi-fied by thin layer chromatography.
Er,lpirical formu1a: C24H47NNa O5e; ~W: 483-54 Example 4 1,2-Dipentadecylmethylidene-glycerol-3-phosphoryl-N-acrylamido-ethanolamine The title compound is formed by reacting 1,2-dipentadecylmethylidene-glycerol-3-phosphroyl-ethanol-amine with acrylyl chloride by the procedure in Example 1. .
Empirical formula: C39H75NNaO7P; MS: 723.97 I J 67~33~
C% H~ N% P~
calculated:~4.70 10.44 1.93 4.2~
found: 65.10 10.28 1.89 4.14 Example 5 N-Acrylamido-cephalin The title compound is formed by the procedure of Example 1, by reacting cephalin isolated from eggs with acrylyl chloride. The compound is identified by thin layer chromatography.
Example 6 Octadecylphosphoryl-1,3-propanediol methacrylate The title cornpound is forrned by the procedure of Example 2~ by reacting octadecylphosphoryl-1,3-propane-diol with methacrylyl chloride, Emp rical formula: C25H4~NaO6P; MW; 498.60 C% H% P%
calculated: 60.22 9.70 6.21 found: 58.97 9.4~ 6.02 Example 7 Palmitoyl-1,3-propanediol-phosphoryl-N,N-dimethyl-N-acryloyl)-ethyl~ -ethanolamine The title compound is formed by the procedure of Example 2, and the compound is identified by thin layer chromatography.
1 ~ 67838 --~o--Empirical formula C28H54N8P; i~lW: 563-69 Exarnple 3 1,2-Dimyristolyl-sn-glycerol-3-phosphoryl-1,3-propane-diol methacrylate - The title compound is formed by the procedure of Example 1, by reacting 1,2-diMyristoyl-sn-glycerol-3-phosphoryl-1,3-propanediol with r,lethacrylyl chloride.
The compound is identified by thin layer chromatography.
Empirical formula: C38H70NaO10 ;
Example 9 1,2-Dimyristoyl-sn-glycerol-3-phosphorylglycerol mono-methacrylate The title cornpound is formed by the procedure of Example 2, by reacting 1,2-diMyristoyl-sn-glycerol-3-phosphoryl-glycerol with methacrylyl chloride.
`Empirical formula: C38H70NaOll ;
C% H~ P%
calculated: 60.29 9.32 4.09 found: 59.73 9.22 ~.12 In the following Examples 10 to 12, the polymer-izable radical is introduced into the phospholipid com-pound of the phospholipid analogue by a procedure anala-gous to the procedures given in the above exa~ples, after removal of the protective group (n) by appropriate reactions (hydrogenolysis, acid splitting).
I ~ 6~3~
Example 10 (16-0-Acryloyl)-hexadecanoyl-1,3-propanediol-phosphoryl-choline This compound is formed by reacting 16-hydroxy-hexadecanoyl-1,3-propanediol-phosphorylcholine with acrylyl chloride.
Ernpirical formula: C27Hs2No8o~l~2o; ~ ; 567-69 C%H% N% P%
calculated: 57.129.59 2.47 5.46 found~ 56.92 9.33 - 2.32 S.23 Example 11 1,2-Di-(16-0-acryloyl)-hexadecanoyl-rac-glycerol-3-phos-phorylcholine The title compound is formed by reacting 1,2-di-(16-hydroxy)-hexadecanoyl-rac-glycerol-3-phosphorylchol-ine with acrylyl chloride. The compound is identified by thin layer chrornatography.
Empirical formula: C44H84N012P.H20;
Example 12 (12-l~Jethacryloyl)-octadecanoyl-1,3-propanediol-phosphor-ylcholine The title compound is formed by reacting 12-hydroxystearoyl-1,3-propanediol--phosphorylcholine with methacrylyl chloride. The compound is identified by thin layer chromatography.
.~
~ J 6~38 Empirical formula: C30H58No8o-H2o;
The following Examples 13 to 18 illustrate the preparation of the polymeric phospholipids according to Example 13 B10CK polymerization The general procedure comprises adding 10 to 20 mg (1 to 2% by weight~ of dibenzoy7 peroxide or an equal amount of ~ azoiso~utyronitrile to 1 g of the rnolten monomer (the acryl or methacryl compounds with an alkyl chain are present as highly viscous oils at room ternpera-ture, whilst the compounds with two long-chain alkyl radicals melt in the range between 20 and 50C), whilst stirring. This mixture is then polymerized in a closed reaction vessel under a nitrogen atmosphere at 50 to 60C for 12 to 24 hours. The solid product is comrninuted, and boiled up several times with a chloro-~orm/methanol mixture (1/1, V/V), until no further mono-mer can be detected in the supernatant liquid by thin layer chromatography. The yields are 50 to 95~ of theory, depending on the polymerization temperature and reaction time.
In the abovementioned general procedure, at a polymerization teinperature of 60C and with a polymer-ization time of 30 seconds, using dibenzoyl peroxide as the initiator, poly-(palmitoyl-2,2-dimethyl- 1,3-propane-1 1 67~
diol-phosphorylethanolamino)-methacrylamide is formed in a yield of 87% of theory.
Empirical formula: (C27H51NNaP)p; MW: p. (555 65) C%H~ N% P~
calculated: 5~.25 9.42 2.52 5.56 found: 58.46 8.75 2.20 4.75 Example 14 Solution polymerization Solution polymerization is generally carried out by a procedure in which 1 g of the monomer is dissolved either in 10 ml of dioxane or in 10 ml of ethyl acetete, and 10 mg (1% by weight) of dibenzoyl ~eroxide (or al-ternatively ~,~-azobisisobutyronitrile) are added. The honogeneous solution is then heated to 50C in a closed vessel under a nitrogen atmosphere for 24 hours. The resulting highly viscous solution is then poured into 150 ml of acetone, whereupon the polymeric product is precipitated, and the precipitate is filtered off and dried in a vacuum desiccator. The yields are 70 to 90% of theory.
Poly-(octadecyl-phosphorylglycerol) methacrylate is formed by applying the procedure described above.
Empirical formula: (C25H49O7P);; MW: p. (4~2.64) 1 1 B783~
-2~-C% H% P%
calculated;60.95 10.08b . 25 found: 60,02 9.55 6.23 Example 15 Poly-(1,2-dipalmitoyl-rac-glycerol-3-phosphoryl-1,3-pro~anediol)methacrylate The title compound is formed by the procedure of Example 14.
Empirical formula: ~C42H78NaOl~P) ; ~ p.(797.0) C% H~ P%
calculated: 63.2Y 9.86 3.87 found: 62.57 9.62 3.79 Example 16 Poly-(palmitoyl-2,2-dimethyl-1,3-propanediol-phosphoryl-ethanolaMino)-methacrylamide The title compound is formed by the procedure of Example 14.
Empirical formula: (C27H51NNaO7P)p; MW: p.(555.65) C% H% W% P~
calculated:58.25 9.42 2.52 5,56 found: 57.41 9.06 2.33 4.72 58.88 9.95 4.17 5.61 Example 17 Poly-(1,2-dimyristoyl-sn-glycerol-3-phosphorylethanol-amino)-acrylamide ~`!
..
I J 67~338 The title compound is formed by the procedure of Example 14.
Empirical formula: (C36H67Ni~aO9P~p; ~w p.(712.87) C~ H~ N~ p%
calculated: 60.65 9.62 1.96 4.35 found: 59.99 9.25 2.7S 4.03 Example 18 Emulsion polymerization A) Emulsion polymerization triggered off by heat 5 x 10 4 moles of the monomer are emulsified in 100 ml of aqueous buffer solution (~hosphate buffer with a pH value of 7.0), whilst sha~ing vigorously in a nitrogen atmosphere. 10 to 20 mg of potassium peroxy-disulfate are then added to the emulsion and the flask is flushed again with a vigorous stream of nitrogen and, after being closed, is heated to a temperature of 60C
in a shaking watérbath for 12 to 1~ hours. The pro-gress of the polymerization reaction is followed by thin layer chromatography (solvent system chloroforin/methanol/
25% strength aqueous ammonia (65/15/1)). Chloroform extracts of samples of the aqueous reaction mixture are used for this. The conversion is estimated from the thin layer chromatogram.
~ ~ `
~ 1 67~3fl B) Emulsion polymeri~ation triggered off photochemic-ally 5 x 10 4 moles of the monomer are emulsified in
10~ ml of a 5 x 10 3~ strength aqueous solution of the di-~a salt of riboflavin. The flask containing the emulsion is temperature-controlled by water flowing round it. The emulsion is then irradiated with a 1000 W
daylight lamp for 30 minutes. During this period, about 80% of the monomer polymer~i~es. The conversion is monitored by thin layer chromatography. The choice of reaction temperature plays an important part in this emulsion polymerization triggered off photochemically.
Using the procedures described above and the monorners given in Examples 14 to 17, the corresponding polymers can be formed.
Example 19 Poly-~octadecylphosphoryl-glycerol) methacrylate micro-capsules containing fluorescein.
2.5 g (~ x 10 3 moles) of octadecylphosphoryl-glycerol mono-methacrylate are dissolved in 100 ml of chlorororm and the material is evaporated to dryness at room temperature under a waterpump vacuum such that the inside of the 1 1 round-bottomed flask is covered with a ~,~
1 ~ ~7838 uniform layer of the monomer. The flasl~ is then char-ged with 500 ml of a 0.1 M sodium chloride solution which contains 165 mg (5 x 10 4 moles) of fluorescein and has been adjusted to a pH value of 7-8 with sodium hydroxide. After adding 50 ml of potassium peroxy-disulfate as an initiator of free radical polymerization (the initiator being employed in an amount of ~%, rela-tive to the monomer) and flushing the flasK with a vigor-ous stream of nitrogen, ~he ~lask is closed tight and the reaction mixture is heated to 60C in a shaking waterbath for ~ hours. 3U ml of the resulting reaction mixture are then transferred, in order to remove the fluorescein which has not been encapsulated, to a dialy-sis tube of regenerated cellulose (which is permeable to substances with a molecular weight of more than 15,000) and the material is dialyzed against four portions of 1 :
1 of 0.1 M sodiu~n chloride solution for 48 hours. The microcapsules obtained in this manner are filled with fluorescein. Their size can be deterTnined by fluores-cent microscopy and by electron microscopy. The diam-eter of these microcapsules is ~.05 to 10 um. It is possible to separate these r,licrocapsules into various size classes by chromatography.
~1 1 1 67~338 -2~-From the above example, it can be clearly seen that, with the aid of the procedure according to the in-vention, it is possible to form stable microcapsules under very mild conditions, so that even sensitive sub-stances, such as enzymes, can be encapsula~ed under gentle conditions, which was not possible with the aid of the hitherto customary formation of microcapsules by interfacial polymerization of polyamides.
, . ' - ' .
daylight lamp for 30 minutes. During this period, about 80% of the monomer polymer~i~es. The conversion is monitored by thin layer chromatography. The choice of reaction temperature plays an important part in this emulsion polymerization triggered off photochemically.
Using the procedures described above and the monorners given in Examples 14 to 17, the corresponding polymers can be formed.
Example 19 Poly-~octadecylphosphoryl-glycerol) methacrylate micro-capsules containing fluorescein.
2.5 g (~ x 10 3 moles) of octadecylphosphoryl-glycerol mono-methacrylate are dissolved in 100 ml of chlorororm and the material is evaporated to dryness at room temperature under a waterpump vacuum such that the inside of the 1 1 round-bottomed flask is covered with a ~,~
1 ~ ~7838 uniform layer of the monomer. The flasl~ is then char-ged with 500 ml of a 0.1 M sodium chloride solution which contains 165 mg (5 x 10 4 moles) of fluorescein and has been adjusted to a pH value of 7-8 with sodium hydroxide. After adding 50 ml of potassium peroxy-disulfate as an initiator of free radical polymerization (the initiator being employed in an amount of ~%, rela-tive to the monomer) and flushing the flasK with a vigor-ous stream of nitrogen, ~he ~lask is closed tight and the reaction mixture is heated to 60C in a shaking waterbath for ~ hours. 3U ml of the resulting reaction mixture are then transferred, in order to remove the fluorescein which has not been encapsulated, to a dialy-sis tube of regenerated cellulose (which is permeable to substances with a molecular weight of more than 15,000) and the material is dialyzed against four portions of 1 :
1 of 0.1 M sodiu~n chloride solution for 48 hours. The microcapsules obtained in this manner are filled with fluorescein. Their size can be deterTnined by fluores-cent microscopy and by electron microscopy. The diam-eter of these microcapsules is ~.05 to 10 um. It is possible to separate these r,licrocapsules into various size classes by chromatography.
~1 1 1 67~338 -2~-From the above example, it can be clearly seen that, with the aid of the procedure according to the in-vention, it is possible to form stable microcapsules under very mild conditions, so that even sensitive sub-stances, such as enzymes, can be encapsula~ed under gentle conditions, which was not possible with the aid of the hitherto customary formation of microcapsules by interfacial polymerization of polyamides.
, . ' - ' .
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a polymerizable phospholipid of the general formula I
(CH2 = ? - ? -) n - A I
wherein n denotes an integer with a value from 1 to 6, R1 denotes a hydrogen atom or a methyl group and A
denotes the radical, bonded via the polar or apolar region of the molecule, of a phospholipid or phospholipid analogue of the general formula II
wherein R represents the liphophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospholipid molecule, in which a reacting acrylic acid derivative of the general formula V
CH2 = ? - ? - X IV
wherein X represents a halogen atom, a hydroxyl group or another easily replaceable molecular group and represents a hydrogen atom or a methyl group, is subjected to a condensation reaction with a phospholipid of the general formula II
in which R and Z are as defined above.
(CH2 = ? - ? -) n - A I
wherein n denotes an integer with a value from 1 to 6, R1 denotes a hydrogen atom or a methyl group and A
denotes the radical, bonded via the polar or apolar region of the molecule, of a phospholipid or phospholipid analogue of the general formula II
wherein R represents the liphophilic portion of the phospholipid molecule and Z represents the hydrophilic portion of the phospholipid molecule, in which a reacting acrylic acid derivative of the general formula V
CH2 = ? - ? - X IV
wherein X represents a halogen atom, a hydroxyl group or another easily replaceable molecular group and represents a hydrogen atom or a methyl group, is subjected to a condensation reaction with a phospholipid of the general formula II
in which R and Z are as defined above.
2. A polymerizable phospholipid as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process as claimed in claim 1 for the preparation of a polymerizable phospholipid of the formula I as set forth in claim 1 wherein n and R1 are as defined in claim 1 and A represents the radical of a phospholipid which is isolated from naturally occurring material and contains functional groups from which derivatives can be formed (alcohol groups or amino groups).
4. A polymerizable phospholipid of the formula I
as set forth in claim 1 wherein n and R1 are as defined in claim 1 and A is as defined in claim 3, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
as set forth in claim 1 wherein n and R1 are as defined in claim 1 and A is as defined in claim 3, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 wherein the polymerizable group is bonded in the polar region Z of the phospholipid molecule, of the general formula III
R - P04H - Z - (- ? - ? = CH2)n III
in which R
A) represents the radical of a monohydric, optionally halogenated and/or unsaturated alcohol;
B) represents the radical of a compound formed by monosubstitution of alkanediols, with etherification or esterification;
C) represents the radical of a compound which contains ether groups which are unstable to acid and is formed by monosubstitution of alkanediols, with etherification;
D) represents the radical of a compound which contains ether groups which can be split off by catalytic hydrogenolysis and is formed by monosubstitution of alkanediols, with etherification;
E) represents the radical of a glycerol derivative with two etherified and/or esterified alcohol groups;
F) represents the radical of a glycerol derivative which has two ether groups which are unstable to acid;
G) represents the radical of a glycerol derivative which contains ether groups which can be split off by catalytic hydrogenolysis and, if appropriate, alkyl ether groups;
H) represents the radical of a phenol of which the free hydroxyl groups are etherified or esterified;
I) represents the radical of a phenol of which the free hydroxyl groups have been converted into ether groups which are unstable to acid;
J) represents the radical of a polyol of which the free hydroxyl groups have been converted into ether groups which can be split off by catalytic hydrogenolysis;
or K) represents the radical of a lipophilic alcohol, and Z
denotes a group of the general formula 1) -(CH2)a-NH- in which a has a value from 2 to 10 2) -(CH2)b-O- in which b has a value from 2 to 10 3) -(CH2)-(CHOH)c-CH2-O- in which c has a value from 1 to 4, in which x and y 4) -(CH2)X-?+-(cH2)y-O- independently of one another can assume values from 2 to 10 5) -CH2-?-NH-or in which x and y 6) independently of one another can assume values from 2 to 10 n denotes an integer with a value from 1 to 6 and denotes, a hydrogen atom or a methyl group.
R - P04H - Z - (- ? - ? = CH2)n III
in which R
A) represents the radical of a monohydric, optionally halogenated and/or unsaturated alcohol;
B) represents the radical of a compound formed by monosubstitution of alkanediols, with etherification or esterification;
C) represents the radical of a compound which contains ether groups which are unstable to acid and is formed by monosubstitution of alkanediols, with etherification;
D) represents the radical of a compound which contains ether groups which can be split off by catalytic hydrogenolysis and is formed by monosubstitution of alkanediols, with etherification;
E) represents the radical of a glycerol derivative with two etherified and/or esterified alcohol groups;
F) represents the radical of a glycerol derivative which has two ether groups which are unstable to acid;
G) represents the radical of a glycerol derivative which contains ether groups which can be split off by catalytic hydrogenolysis and, if appropriate, alkyl ether groups;
H) represents the radical of a phenol of which the free hydroxyl groups are etherified or esterified;
I) represents the radical of a phenol of which the free hydroxyl groups have been converted into ether groups which are unstable to acid;
J) represents the radical of a polyol of which the free hydroxyl groups have been converted into ether groups which can be split off by catalytic hydrogenolysis;
or K) represents the radical of a lipophilic alcohol, and Z
denotes a group of the general formula 1) -(CH2)a-NH- in which a has a value from 2 to 10 2) -(CH2)b-O- in which b has a value from 2 to 10 3) -(CH2)-(CHOH)c-CH2-O- in which c has a value from 1 to 4, in which x and y 4) -(CH2)X-?+-(cH2)y-O- independently of one another can assume values from 2 to 10 5) -CH2-?-NH-or in which x and y 6) independently of one another can assume values from 2 to 10 n denotes an integer with a value from 1 to 6 and denotes, a hydrogen atom or a methyl group.
6. A polymerizable phospholipid of the formula I
as defined in claim 1, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
as defined in claim 1, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process as claimed in claim 5 wherein R
A) represents the radical of hexanol, decanol, hexa-decanol, eicosanol, hexacosanol, cyclohexanol, bromo-l-hexanol, 10-bromo-1-decanol, 16-bromo-1-hexa-decanol or 9-octadecen-1-ol;
B) represents the radical of acetylglycol, ethylglycol, decanoylglycol, decylglycol, hexadecanoylglycol, hexadecylglycol, eicosanoylglycol or eicosylglycol or of a monoacyl or monoalkyl derivative of l,3-propane-diol, 1,2-propanediol, 1,6-hexanediol, l,10-decane-diol or l,16-hexadecanediol, the acyl and alkyl groups of the monoacyl or monoalkyl derivatives each containing 1 to 22 carbon atoms;
C) represents the radical of l-tritylglycol, l-tetra-hydropryanylglycol, l-trityl-1,3-propanediol, 1-K) represents the radical of cholesterol, retinol, and rosterone, ergosterol, a steroid alcohol, an isoprenoid alcohol or a carotenoid alcohol.
A) represents the radical of hexanol, decanol, hexa-decanol, eicosanol, hexacosanol, cyclohexanol, bromo-l-hexanol, 10-bromo-1-decanol, 16-bromo-1-hexa-decanol or 9-octadecen-1-ol;
B) represents the radical of acetylglycol, ethylglycol, decanoylglycol, decylglycol, hexadecanoylglycol, hexadecylglycol, eicosanoylglycol or eicosylglycol or of a monoacyl or monoalkyl derivative of l,3-propane-diol, 1,2-propanediol, 1,6-hexanediol, l,10-decane-diol or l,16-hexadecanediol, the acyl and alkyl groups of the monoacyl or monoalkyl derivatives each containing 1 to 22 carbon atoms;
C) represents the radical of l-tritylglycol, l-tetra-hydropryanylglycol, l-trityl-1,3-propanediol, 1-K) represents the radical of cholesterol, retinol, and rosterone, ergosterol, a steroid alcohol, an isoprenoid alcohol or a carotenoid alcohol.
8. A polymerizable phospholipid of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.
9. A process as claimed in claim 1 for the preparation of a polymerizable phospholipid in which the polymerizable group is bonded in the apolar region R of the molecule, of the general formula IV
(CH2 = ? - ? - )n - R P04H-z IV
in which R
A) represents an alkyl radical which is at least bifunctional and has 6 to 22 carbon atoms;
B) represents the radical of a monosubstituted alkane-diol, amino alcohol or alkanediamine which has 2 to 6 carbon atoms, which carry a substituent which has 6 to 22 carbon atoms and an ester, ether or amide linkage, and which contains at least one additional amino or alcohol group;
C) represents the radical of a monosubstituted or disubstituted glycerol derivative which carries tetrahydropyranyl-1,3-propanediol, 1-trityl-1,6-hexanediol, 1-tetrahydropyranyl-1,6-hexanediol, 1-trityl-l,10-decanediol, l-tetrahydropyranyl-1,10-decanediol, 1-trityl-1,16-hexadecanol or 1-tetra-hydropyranyl-1,16-hexadecanol;
D) represents the radical of 1 benzylglycol, 1-benzyl-1,3-propanediol, 1-benzyl-1,2 propanediol, 1-benzyl-1,6-hexanediol, 1-benzyl-1,10-decanediol or 1-benzyl-1,16-hexadecanediol;
E) represents the radical of 1,2-dimethylglycerol, 1,3-dimethylglycerol, l,2-diacetylglycerol, 1,3-diacetyl-glycerol, 1,2-diethylglycerol or 1,3-diethylglycerol or of the corresponding esters with higher fatty acids, of the corresponding ethers with higher alkyl radicals, or of the corresponding mixed esters, mixed ethers or mixed ester/ether compounds;
F) represents the radical of 1,3-ditritylglycerol or 1,2-isopropylideneglycerol;
G) represents the radical of l-benzyl-2-lauroyl-glycerol, 1-lauroyl-2-benzyl-glycerol, 1-benzyl-2-palmitoyl-glycerol, 1-palmitoyl-2-benzyl-glycerol, 1-benzyl-2-arachoyl-glycerol or 1-arachoyl-2-benzyl-glycerol, or of the corresponding alkyl ethers with low-molecular alkyl groups;
H) represents the radical of erythritol, arabitol, xylitol, adonitol, mannitol, sorbitol or dulcitol;
or substituents as mentioned under B); or D) represents the radical of a monosubstituted or polysubstituted (nOH-l) pvlyol which carries substituents as mentioned under B), and Z denotes a group of the general formula 1) -(CH2)a-NH2 in which a has a value from 2 to 10, 2) -(CH2)b-OH in which b has a value from 2 to 10 3) -(CH2)-(CHOH)c-CH2-OH in which c has a value from 1 to 4, in which x and y 4) -(CH2)x-?+-(CH2)y-OH independently of one another can assume values from 2 to 10, 5) -CH2-1?-HN2 in which x and y 6) -(CH2)X-?+-(CH2)y-NH independently of one another can assume values from 2 to 10, 7) -(CH2)d-?CH3H2 in which d denotes an integer from 2 to 10, 8) -(CH2)e-?(CH3)2H in which e denotes an integer from 2 to 10, 9) -(CH2)f-?(CH3)3 in which f denotes an integer from 2 to 10, 10) -(CH2)g-H in which g denotes an integer from 2 10 10, or 11) a hydrogen atom, n denotes an integer with a value from 1 to 6 and R1 denotes a hydrogen atom or a methyl group.
(CH2 = ? - ? - )n - R P04H-z IV
in which R
A) represents an alkyl radical which is at least bifunctional and has 6 to 22 carbon atoms;
B) represents the radical of a monosubstituted alkane-diol, amino alcohol or alkanediamine which has 2 to 6 carbon atoms, which carry a substituent which has 6 to 22 carbon atoms and an ester, ether or amide linkage, and which contains at least one additional amino or alcohol group;
C) represents the radical of a monosubstituted or disubstituted glycerol derivative which carries tetrahydropyranyl-1,3-propanediol, 1-trityl-1,6-hexanediol, 1-tetrahydropyranyl-1,6-hexanediol, 1-trityl-l,10-decanediol, l-tetrahydropyranyl-1,10-decanediol, 1-trityl-1,16-hexadecanol or 1-tetra-hydropyranyl-1,16-hexadecanol;
D) represents the radical of 1 benzylglycol, 1-benzyl-1,3-propanediol, 1-benzyl-1,2 propanediol, 1-benzyl-1,6-hexanediol, 1-benzyl-1,10-decanediol or 1-benzyl-1,16-hexadecanediol;
E) represents the radical of 1,2-dimethylglycerol, 1,3-dimethylglycerol, l,2-diacetylglycerol, 1,3-diacetyl-glycerol, 1,2-diethylglycerol or 1,3-diethylglycerol or of the corresponding esters with higher fatty acids, of the corresponding ethers with higher alkyl radicals, or of the corresponding mixed esters, mixed ethers or mixed ester/ether compounds;
F) represents the radical of 1,3-ditritylglycerol or 1,2-isopropylideneglycerol;
G) represents the radical of l-benzyl-2-lauroyl-glycerol, 1-lauroyl-2-benzyl-glycerol, 1-benzyl-2-palmitoyl-glycerol, 1-palmitoyl-2-benzyl-glycerol, 1-benzyl-2-arachoyl-glycerol or 1-arachoyl-2-benzyl-glycerol, or of the corresponding alkyl ethers with low-molecular alkyl groups;
H) represents the radical of erythritol, arabitol, xylitol, adonitol, mannitol, sorbitol or dulcitol;
or substituents as mentioned under B); or D) represents the radical of a monosubstituted or polysubstituted (nOH-l) pvlyol which carries substituents as mentioned under B), and Z denotes a group of the general formula 1) -(CH2)a-NH2 in which a has a value from 2 to 10, 2) -(CH2)b-OH in which b has a value from 2 to 10 3) -(CH2)-(CHOH)c-CH2-OH in which c has a value from 1 to 4, in which x and y 4) -(CH2)x-?+-(CH2)y-OH independently of one another can assume values from 2 to 10, 5) -CH2-1?-HN2 in which x and y 6) -(CH2)X-?+-(CH2)y-NH independently of one another can assume values from 2 to 10, 7) -(CH2)d-?CH3H2 in which d denotes an integer from 2 to 10, 8) -(CH2)e-?(CH3)2H in which e denotes an integer from 2 to 10, 9) -(CH2)f-?(CH3)3 in which f denotes an integer from 2 to 10, 10) -(CH2)g-H in which g denotes an integer from 2 10 10, or 11) a hydrogen atom, n denotes an integer with a value from 1 to 6 and R1 denotes a hydrogen atom or a methyl group.
10. A polymerizable phospholipid of the formula I
as defined in claim 1, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
as defined in claim 1, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19803010185 DE3010185A1 (en) | 1980-03-17 | 1980-03-17 | POLYMERIZABLE PHOSPHOLIPIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR THE PRODUCTION OF POLYMER PHOSPHOLIPIDS |
DEP3010185.0 | 1980-03-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1167838A true CA1167838A (en) | 1984-05-22 |
Family
ID=6097444
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000373059A Expired CA1167838A (en) | 1980-03-17 | 1981-03-16 | Polymerizable phospholipids and a process for their preparation, polymeric phospholipids and a process for their preparation, and the use of the polymeric phospholipids |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0036155A3 (en) |
JP (1) | JPS56152816A (en) |
CA (1) | CA1167838A (en) |
DE (1) | DE3010185A1 (en) |
ES (2) | ES500256A0 (en) |
IL (1) | IL62369A0 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5648442A (en) * | 1991-07-05 | 1997-07-15 | Biocompatibles Limited | Polymeric surface coatings |
US6090901A (en) * | 1991-07-05 | 2000-07-18 | Biocompatibles Limited | Polymeric surface coatings |
US6420453B1 (en) | 1990-10-29 | 2002-07-16 | Biocompatibles Limited | Contact lens material |
US6743878B2 (en) | 1991-07-05 | 2004-06-01 | Biocompatibles Uk Limited | Polymeric surface coatings |
CN103917548A (en) * | 2011-06-24 | 2014-07-09 | 生物相互作用有限公司 | Biocompatible, biomimetic ampholyte materials |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60179408A (en) * | 1984-02-24 | 1985-09-13 | Oki Electric Ind Co Ltd | Compound having phospholipid-like structure and its polymer and production thereof |
CA1243038A (en) * | 1984-12-28 | 1988-10-11 | Kazuhiko Suzuki | Polymerizable liposome-forming lipid, method for production thereof, and use thereof |
JPS61155336A (en) * | 1984-12-28 | 1986-07-15 | Terumo Corp | Medical carrier |
JPS61215398A (en) * | 1985-03-20 | 1986-09-25 | Kao Corp | Phosphoric ester |
US4736051A (en) * | 1985-03-20 | 1988-04-05 | Kao Corporation | Process for the preparation of an alkali metal salt of a diester phosphoric acid |
DE3623068A1 (en) * | 1985-07-12 | 1987-01-22 | Kao Corp | POLYMERS AND COPOLYMERS CONTAINING A PHOSPHATE GROUP AND PROCESS FOR THEIR MANUFACTURING |
JPS638391A (en) * | 1986-06-27 | 1988-01-14 | Terumo Corp | Polymerizable beta-glycerophospholipid and production thereof |
JPS63222185A (en) * | 1987-03-11 | 1988-09-16 | Oki Electric Ind Co Ltd | Compound having phospholipid analogous structure, polymer and production thereof |
JPS6386704A (en) * | 1987-05-21 | 1988-04-18 | Oki Electric Ind Co Ltd | Polymer from compound having phospholipid-like structure |
JPH04283207A (en) * | 1991-03-13 | 1992-10-08 | Kao Corp | Vesicle and polymer vesicle |
US5466853A (en) * | 1992-07-23 | 1995-11-14 | Nof Corporation | Diester monomer, its polymer, water-containing soft contact lens, and processing solution for contact lens |
GB9301701D0 (en) * | 1993-01-28 | 1993-03-17 | Biocompatibles Ltd | New zwitterionic materials |
FR2717427B1 (en) * | 1994-03-17 | 1996-04-19 | Renault | Motor vehicle air conditioning system. |
WO2021107141A1 (en) * | 2019-11-29 | 2021-06-03 | 国立大学法人徳島大学 | Zwitterion compound and production method and use for same |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6021599B2 (en) * | 1977-10-28 | 1985-05-28 | 株式会社クラレ | 2-methacryloxyethylphosphorylcholine |
-
1980
- 1980-03-17 DE DE19803010185 patent/DE3010185A1/en not_active Withdrawn
-
1981
- 1981-03-07 EP EP81101675A patent/EP0036155A3/en not_active Withdrawn
- 1981-03-11 ES ES500256A patent/ES500256A0/en active Granted
- 1981-03-11 ES ES500259A patent/ES8201591A1/en not_active Expired
- 1981-03-15 IL IL62369A patent/IL62369A0/en unknown
- 1981-03-16 CA CA000373059A patent/CA1167838A/en not_active Expired
- 1981-03-17 JP JP3736481A patent/JPS56152816A/en active Pending
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6420453B1 (en) | 1990-10-29 | 2002-07-16 | Biocompatibles Limited | Contact lens material |
US6423761B1 (en) | 1990-10-29 | 2002-07-23 | Biocompatibles Limited | Contact lens material |
US5648442A (en) * | 1991-07-05 | 1997-07-15 | Biocompatibles Limited | Polymeric surface coatings |
US5783650A (en) * | 1991-07-05 | 1998-07-21 | Biocompatibles Limited | Polymeric surface coatings |
US6090901A (en) * | 1991-07-05 | 2000-07-18 | Biocompatibles Limited | Polymeric surface coatings |
US6743878B2 (en) | 1991-07-05 | 2004-06-01 | Biocompatibles Uk Limited | Polymeric surface coatings |
US7160953B2 (en) | 1991-07-05 | 2007-01-09 | Biocompatibles Uk Limited | Polymeric surface coatings |
CN103917548A (en) * | 2011-06-24 | 2014-07-09 | 生物相互作用有限公司 | Biocompatible, biomimetic ampholyte materials |
Also Published As
Publication number | Publication date |
---|---|
DE3010185A1 (en) | 1981-09-24 |
ES8201590A1 (en) | 1981-12-16 |
ES500259A0 (en) | 1981-12-16 |
EP0036155A2 (en) | 1981-09-23 |
JPS56152816A (en) | 1981-11-26 |
IL62369A0 (en) | 1981-05-20 |
ES8201591A1 (en) | 1981-12-16 |
ES500256A0 (en) | 1981-12-16 |
EP0036155A3 (en) | 1982-01-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1167838A (en) | Polymerizable phospholipids and a process for their preparation, polymeric phospholipids and a process for their preparation, and the use of the polymeric phospholipids | |
CA1222254A (en) | Polymerized vesicles and compounds for their preparation | |
Hupfer et al. | Liposomes from polymerizable phospholipids | |
AU737980B2 (en) | Novel polymerizable fatty acids, phospholipids and polymerized liposomes therefrom | |
Regen et al. | Polymerized phosphatidylcholine vesicles. Synthesis and characterization | |
US5366881A (en) | Polymerizable lipids for preparing vesicles that controllably release an encapsulant | |
DE2611143A1 (en) | BIOLOGICAL MATERIAL, ITS USE AND MANUFACTURING | |
NO324068B1 (en) | Contrast agents for use in diagnostic ultrasound examinations and fluid dispersion of vesicles and their preparation, as well as oil-in-water emulsion for use in the preparation | |
JPS6333414B2 (en) | ||
US4861521A (en) | Polymerizable liposome-forming lipid, and method for production thereof | |
US4587055A (en) | Polymerized vesicles and compounds for their preparation | |
JP2009298817A (en) | Phosphatidyl oligoglycerol | |
EP0245799B1 (en) | Electromagnetic wave-sensitive material and bio-adaptable surface treating agent | |
EP0251229A1 (en) | Polymerizable beta-glycerophospholipid and method for production thereof | |
EP0055235B1 (en) | Gel product for separation | |
DE4127657B4 (en) | Pearled polyvinyl alcohol gels for the purification and separation of biological fluids, process for their preparation and use | |
JPH0710874B2 (en) | Polymerizable phospholipid | |
JPH068302B2 (en) | Polymerizable phospholipid compound | |
JPH0148777B2 (en) | ||
JPH0261957B2 (en) | ||
JPH078879B2 (en) | Polymerizable phospholipid compound | |
WO2023112939A1 (en) | Method for purifying composition | |
JPH0572915B2 (en) | ||
US7037997B1 (en) | Vinyl monomer, support matrix and its preparation | |
JPH0148776B2 (en) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry |