JPH0437731B2 - - Google Patents
Info
- Publication number
- JPH0437731B2 JPH0437731B2 JP60295688A JP29568885A JPH0437731B2 JP H0437731 B2 JPH0437731 B2 JP H0437731B2 JP 60295688 A JP60295688 A JP 60295688A JP 29568885 A JP29568885 A JP 29568885A JP H0437731 B2 JPH0437731 B2 JP H0437731B2
- Authority
- JP
- Japan
- Prior art keywords
- membrane component
- liposome
- volatile organic
- substance
- liposomes
- 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 - Lifetime
Links
- 239000002502 liposome Substances 0.000 claims description 48
- 239000012528 membrane Substances 0.000 claims description 31
- 239000000126 substance Substances 0.000 claims description 29
- 239000003960 organic solvent Substances 0.000 claims description 19
- 238000001694 spray drying Methods 0.000 claims description 16
- 239000003125 aqueous solvent Substances 0.000 claims description 15
- 239000008240 homogeneous mixture Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 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 description 14
- 239000000725 suspension Substances 0.000 description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 11
- 239000008103 glucose Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 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 description 8
- 238000000034 method Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 235000012000 cholesterol Nutrition 0.000 description 7
- 239000011812 mixed powder Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- -1 sphingomyelin Chemical compound 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 230000000717 retained effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 3
- FZWBNHMXJMCXLU-UHFFFAOYSA-N 2,3,4,5-tetrahydroxy-6-[3,4,5-trihydroxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyhexanal Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OCC(O)C(O)C(O)C(O)C=O)O1 FZWBNHMXJMCXLU-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 3
- 229940093541 dicetylphosphate Drugs 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 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 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 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 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930182558 Sterol Natural products 0.000 description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 2
- 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 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000011162 core material Substances 0.000 description 2
- 229960002086 dextran Drugs 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000002523 gelfiltration Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 239000011824 nuclear material Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 229940083466 soybean lecithin Drugs 0.000 description 2
- 150000003432 sterols Chemical class 0.000 description 2
- 235000003702 sterols Nutrition 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-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
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- DBTMGCOVALSLOR-UHFFFAOYSA-N 32-alpha-galactosyl-3-alpha-galactosyl-galactose Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(OC2C(C(CO)OC(O)C2O)O)OC(CO)C1O DBTMGCOVALSLOR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- RXVWSYJTUUKTEA-UHFFFAOYSA-N D-maltotriose Natural products OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1OC1C(O)C(O)C(O)C(CO)O1 RXVWSYJTUUKTEA-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 description 1
- 102100022624 Glucoamylase Human genes 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
- 239000004471 Glycine Substances 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 108010026389 Gramicidin Proteins 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- QYIXCDOBOSTCEI-UHFFFAOYSA-N alpha-cholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 QYIXCDOBOSTCEI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- 229930002875 chlorophyll Natural products 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
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- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
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- 235000019425 dextrin Nutrition 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
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- 150000002016 disaccharides Chemical class 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- IUAYMJGZBVDSGL-XNNAEKOYSA-N gramicidin S Chemical compound C([C@@H]1C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@H](C(N[C@H](CC=2C=CC=CC=2)C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(C)C)C(=O)N1)C(C)C)=O)CC(C)C)C(C)C)C1=CC=CC=C1 IUAYMJGZBVDSGL-XNNAEKOYSA-N 0.000 description 1
- 229950009774 gramicidin s Drugs 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- FYGDTMLNYKFZSV-UHFFFAOYSA-N mannotriose Natural products OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(OC2C(OC(O)C(O)C2O)CO)C(O)C1O FYGDTMLNYKFZSV-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@H](CO)O[C@@H](O[C@@H]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Classifications
-
- 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
- A61K9/1277—Processes for preparing; Proliposomes
Description
【発明の詳細な説明】 〈産業上の利用分野〉 本発明はリポソームの新規製造法に関する。[Detailed description of the invention] <Industrial application field> The present invention relates to a novel method for producing liposomes.
脂質の閉鎖小胞であるリポソームは、広く生体
膜モデルとしてその物理化学的諸性質の研究に利
用されてきた、一方リポソームはその内部に種々
の薬剤を保持することが可能であるために、ドラ
ツグキヤリヤーとしての応用研究が数多くなされ
ている。 Liposomes, which are closed vesicles of lipids, have been widely used as biological membrane models to study their physicochemical properties.On the other hand, liposomes can hold various drugs inside them, so A lot of applied research has been carried out as a Tsugu carrier.
〈従来技術の説明〉
リポソームの製法としては、最近、特開昭60−
7932号、60−7933号、60−7934号及び60−12127
号などの方法が報告されているが、その数は非常
に少ない。そして多くの研究者により、リポソー
ムの臨床への応用研究がなされているにもかかわ
らず、いまだかつてリポソーム製剤が商品化され
えない一つの大きな要因が工業的生産の困難さに
あると言つても過言ではない。<Description of the prior art> Recently, as a method for producing liposomes, Japanese Patent Application Laid-open No. 1983-
No. 7932, No. 60-7933, No. 60-7934 and No. 60-12127
Although methods such as No. 1 have been reported, the number of them is very small. Despite the fact that many researchers are conducting clinical application research on liposomes, one of the major reasons why liposome preparations have not been commercialized is the difficulty of industrial production. It's not too much to say.
〈発明が解決しようとする問題点〉
本発明者らはリポソームの工業的製法について
鋭意検討した結果、揮発性有機溶媒に不溶で水性
溶媒に可溶な物質、リポソーム膜成分物質及び揮
発性有機溶媒からなり、リポソーム膜成分物質と
揮発性有機溶媒に不溶で水性溶媒に可溶な物質と
の重量比が１：２〜１：2.6の組成物を噴霧乾燥
すると無定型な均一系混合物が得られ、又、該均
一系混合物が水性溶媒に素早く膨潤し、更に分散
させると意外にも均一でかつ薬剤の保持効率のよ
いリポソームを再現性よく製造可能なことを見い
出し本発明を完成した。<Problems to be Solved by the Invention> As a result of intensive studies on the industrial production method of liposomes, the present inventors found that substances that are insoluble in volatile organic solvents and soluble in aqueous solvents, liposome membrane component substances, and volatile organic solvents An amorphous homogeneous mixture is obtained by spray drying a composition in which the weight ratio of the liposome membrane component substance and the substance insoluble in volatile organic solvents and soluble in aqueous solvents is 1:2 to 1:2.6. Furthermore, the present inventors discovered that the homogeneous mixture quickly swells in an aqueous solvent and that by further dispersing it, it is possible to produce liposomes that are surprisingly uniform and have good drug retention efficiency with good reproducibility, thereby completing the present invention.
〈発明の構成〉
本発明は、揮発性有機溶媒に不溶で水性溶媒に
可溶な物質、リポソーム膜成分物質及び揮発性有
機溶媒からなり、リポソーム膜成分物質と揮発性
有機溶媒に不溶で水性溶媒に可溶な物質との重量
比が１：２〜１：2.6の組成物を噴霧乾燥して有
機溶媒を除去し、製した均一系混合物を水性溶媒
中に分散させることを特徴とするリポソームの製
造法に関する。<Configuration of the Invention> The present invention consists of a substance that is insoluble in a volatile organic solvent and soluble in an aqueous solvent, a liposome membrane component substance, and a volatile organic solvent. Liposomes are prepared by spray-drying a composition having a weight ratio of 1:2 to 1:2.6 with a substance soluble in the organic solvent, removing the organic solvent, and dispersing the resulting homogeneous mixture in an aqueous solvent. Regarding manufacturing methods.
リポソーム膜成分物質については、ホスフアチ
ジルコリン、ホスフアチジルエテノールアミン、
ホスフアチジルセリン、ホスフアチジルイノシト
ール、リゾホスフアチジルコリン、スフインゴミ
エリン、卵黄レシチン、大豆レシチン等に代表さ
れるリン脂質の他、糖脂質、ジアルキル型合成界
面活性剤等の一種又は二種以上の混合物が主体と
なる。そして、これに膜安定化剤としてコレステ
ロール、コレスタノール等のステロール類を、荷
電物質としてジセチルホスフエート、ホスフアチ
ジン酸、ガングリオシド、ステアリルアミン等
を、更に酸化防止剤としてα−トコフエロール等
を加えて膜成分物質を形成させても良い。このよ
うなリポソーム膜成分物質の成分の比率は何ら限
定されるべきものではないが、好ましくは脂質１
重量部に対し、ステロール類を０〜１重量部程
度、荷電物質を０〜0.2重量部程度加えるのが適
している。 Regarding liposome membrane component substances, phosphatidylcholine, phosphatidylethenolamine,
In addition to phospholipids represented by phosphatidylserine, phosphatidylinositol, lysophosphatidylcholine, sphingomyelin, egg yolk lecithin, soybean lecithin, etc., one or two types of glycolipids, dialkyl type synthetic surfactants, etc. The main ingredient is a mixture of the above. Then, sterols such as cholesterol and cholestanol are added as membrane stabilizers, dicetyl phosphate, phosphatidic acid, ganglioside, stearylamine, etc. are added as charged substances, and α-tocopherol, etc. are added as antioxidants to form a membrane. Component materials may also be formed. Although the ratio of components of such liposome membrane component substances should not be limited in any way, it is preferable that lipid 1
It is suitable to add about 0 to 1 part by weight of the sterol and about 0 to 0.2 part by weight of the charged substance.
揮発性有機溶媒としては上記リポソーム膜成分
物質が溶解可能でかつ低沸点のものが好ましく、
具体例としてはクロロホルム、トリクロロエタ
ン、アセトン、エタノール等があげられる。これ
らの揮発性有機溶媒は単独もしくは混合して用い
られ、混合して用いる場合には相互に混和し合う
ものが好ましい。このような有機溶媒の膜成分物
質に対する使用量は、膜成分物質が溶解可能な量
以上であればよく、通常、膜成分物質１重量部に
対して５〜100重量部使用される。 The volatile organic solvent is preferably one that can dissolve the liposome membrane component substance and has a low boiling point;
Specific examples include chloroform, trichloroethane, acetone, and ethanol. These volatile organic solvents may be used alone or in combination, and when used in combination, those that are mutually miscible are preferred. The amount of such an organic solvent to be used with respect to the membrane component material may be at least an amount capable of dissolving the membrane component material, and is usually used in an amount of 5 to 100 parts by weight per 1 part by weight of the membrane component material.
水性溶媒としては、水、生理食塩水、リン酸、
クエン酸等からなる緩衝液、グルコース、マンニ
トール等の糖類の水溶液及びこれらの混合液が使
用可能である。これらの水性溶媒は通常、膜成分
物質１重量部に対して10〜1000重量部使用され
る。 Aqueous solvents include water, physiological saline, phosphoric acid,
Buffer solutions such as citric acid, aqueous solutions of sugars such as glucose and mannitol, and mixtures thereof can be used. These aqueous solvents are usually used in an amount of 10 to 1000 parts by weight per 1 part by weight of the membrane component material.
次に本発明の製造法の具体的操作方法を説明す
る。 Next, a specific operating method of the manufacturing method of the present invention will be explained.
まず、リポソーム膜成分物質を揮発性有機溶媒
に溶解せしめる。一般には膜成分物質は比較的容
易に揮発性有機溶媒に溶解しうるが、加温、攪拌
等の手段を用いれば更に効率が良い。 First, liposome membrane component substances are dissolved in a volatile organic solvent. Generally, membrane component substances can be dissolved in volatile organic solvents relatively easily, but it is more efficient if heating, stirring, or other means are used.
得られた溶液を二流体型、デイスク型等の噴霧
乾燥装置、好ましくは溶媒回収型のものを用いて
噴霧乾燥することにより均一系混合物を得ること
ができる。該均一系混合物とは膜成分物質が均一
に混合したものであり、粉末、油、半固形の状態
で得られる。一般には粉末状に得られた均一系混
合物が膨潤速度の面から好ましく、その粒子径は
なるべく小さい方が望ましい。又、膜成分物質と
揮発性有機溶媒からなる溶液に揮発性有機溶媒に
不溶な物質（以下、核物質と称す。）を添加し、
充分分散させた後、噴霧乾燥すると一層粒子径の
小さい粉末を得ることがある。特に使用するリポ
ソーム膜成分におけるコレステロールの比率が高
い場合及び不飽和脂肪酸よりなるリン脂質を膜成
分物質の脂質成分として用いた場合等には均一系
混合物が油状又は半固形状で得られることが多
い。このような場合には上記核物質を添加するこ
とが望ましい。 A homogeneous mixture can be obtained by spray drying the obtained solution using a two-fluid type or disk type spray drying apparatus, preferably a solvent recovery type. The homogeneous mixture is a uniform mixture of membrane component substances, and is obtained in the form of powder, oil, or semi-solid. In general, a homogeneous mixture obtained in powder form is preferred from the viewpoint of swelling speed, and the particle size is preferably as small as possible. Further, a substance insoluble in the volatile organic solvent (hereinafter referred to as a nuclear substance) is added to the solution consisting of the membrane component substance and the volatile organic solvent,
After sufficient dispersion, spray drying may yield a powder with even smaller particle size. Particularly when the ratio of cholesterol in the liposome membrane component used is high, or when phospholipids made of unsaturated fatty acids are used as the lipid component of the membrane component, a homogeneous mixture is often obtained in an oily or semi-solid form. . In such cases, it is desirable to add the above-mentioned nuclear material.
核物質としては種々のものがあげられるが、中
でも水性溶媒に可溶なものがリポソーム製剤の浸
透圧等の面から好ましく、具体例としてはマンニ
トール、ソルビトール、マルチトース等の糖アル
コール；グルコース、イノシトール等の単糖類；
サツカロース、マルトース、ラクトース等の二糖
類；マルトトリオース等の三糖類；シクロデキス
トリン等の環状オリゴ糖類；デキストリン、デキ
ストラン等の多糖類；グリシン、リジン、グルタ
ミン酸ナトリウム等のアミノ酸類；塩化カリウ
ム、塩化ナトリウム、リン酸塩等の無機塩；クエ
ン酸塩等の有機塩；ポリビニルピロリドン、デキ
ストラン硫酸等の高分子化合物等があげられ、こ
れらは単独もしくは混合して用いてもよい。核物
質は膜成分物質１重量部に対し、通常、２〜2.6
重量部使用される。又、該添加物質の粒子径は
種々のものが使用可能であるが、通常約150μm以
下のものが使用される。 There are various types of nuclear substances, but among them, those soluble in aqueous solvents are preferred from the viewpoint of osmotic pressure of liposome preparations, and specific examples include sugar alcohols such as mannitol, sorbitol, and maltitose; glucose, inositol, etc. monosaccharides;
Disaccharides such as satucarose, maltose, and lactose; Trisaccharides such as maltotriose; Cyclic oligosaccharides such as cyclodextrin; Polysaccharides such as dextrin and dextran; Amino acids such as glycine, lysine, and sodium glutamate; Potassium chloride, sodium chloride , inorganic salts such as phosphate; organic salts such as citrate; and polymeric compounds such as polyvinylpyrrolidone and dextran sulfate. These may be used alone or in combination. The nuclear material is usually 2 to 2.6 parts by weight of the membrane component material.
Parts by weight are used. Further, various particle sizes of the additive substance can be used, but those having a particle size of about 150 μm or less are usually used.
得られる膜成分物質の均一系混合物もしくは膜
成分物質と上記核物質との混合物に水性溶媒を加
えて膜成分物質を膨潤させる。この際、脂質の相
転移温度（以下、TCと称す。）以上に加温すると
膨潤が一層すみやかに進行する。 An aqueous solvent is added to the obtained homogeneous mixture of the membrane component material or the mixture of the membrane component material and the core material to swell the membrane component material. At this time, if the temperature is increased above the phase transition temperature (hereinafter referred to as TC) of the lipid, the swelling will proceed more quickly.
充分膨潤したところで、ホモジナイザー、プロ
ペラミキサー等の通常の乳化に使用される乳化装
置を用いて充分分散させることにより目的とする
リポソームの懸濁液を製造できる。この時やはり
TC以上に加温した方が効率の良いことは言うま
でもない。また、膨潤、分散及び分散終了後の過
程で窒素ガス等の不活性ガスによるバブリングを
行なうことが望ましい。 Once the liposomes are sufficiently swollen, they can be sufficiently dispersed using an emulsifying device commonly used for emulsification, such as a homogenizer or a propeller mixer, to produce the desired liposome suspension. At this time as expected
It goes without saying that heating above TC is more efficient. Furthermore, it is desirable to perform bubbling with an inert gas such as nitrogen gas during the swelling, dispersion, and post-dispersion processes.
本発明のリポソームに保持可能なものとして
は、特に制限はないが、アドリアマイシン、サイ
トシンアラビノシド、メトトレキセートに代表さ
れる制癌剤、アルフオテリシンＢ等に代表される
抗生物質、インシユリン、インターフエロン、グ
ルコアミラーゼに代表されるたんぱく質、デキス
トランに代表される多糖類、DNA、RNAの如き
核酸類、ビタミンＡに代表されるビタミン類等の
他、サリチル酸ナトリウムのような一般薬剤をあ
げることができる。これ等の物質は、水性溶媒に
溶解して用いるが、クロロフイル、グラミシジン
Ｓ、ビタミンＡ等に代表される膜親和性薬剤は膜
成分物質と一緒に有機溶媒中に混合せしめた方が
通常効率が良い。 There are no particular limitations on the substances that can be held in the liposomes of the present invention, including anticancer drugs such as adriamycin, cytosin arabinoside, and methotrexate, antibiotics such as alphatericin B, insulin, interferon, and glucoamylase. In addition to typical proteins, polysaccharides such as dextran, nucleic acids such as DNA and RNA, vitamins such as vitamin A, and general drugs such as sodium salicylate. These substances are used by being dissolved in an aqueous solvent, but membrane-compatible drugs such as chlorophyll, gramicidin S, and vitamin A are usually more efficient when mixed with membrane component substances in an organic solvent. good.
また、同一処方内で薬剤のリポソームへの保持
率を高めるには保持させる薬剤の処方量を少量の
水性溶媒に溶かしこみ、これをまず膜成分物質の
噴霧乾燥後の粉末に加えて、膨潤、分散させ、次
いで水性溶媒に加えて希釈すればよい。 In addition, to increase the retention rate of drugs in liposomes within the same formulation, dissolve the prescribed amount of the drug to be retained in a small amount of aqueous solvent, first add this to the spray-dried powder of the membrane component substance, and swell. It may be dispersed and then diluted by adding to an aqueous solvent.
小さな粒径のリポソーム製剤を製造するには超
音波乳化機、高圧乳化機等を用いても良い。更に
径を均一にするために限外濾過膜法、例えばポリ
カーボネート製メンブラン・フイルターによつて
粒径分布をコントロールすることも可能である。 An ultrasonic emulsifier, a high-pressure emulsifier, etc. may be used to produce a liposome preparation with a small particle size. Furthermore, in order to make the diameter uniform, it is also possible to control the particle size distribution by using an ultrafiltration membrane method, for example, using a polycarbonate membrane filter.
このようにして薬剤を保持した均一粒径のリポ
ソーム製剤が大量にしかも再現性良く得られる。
このリポソーム製剤はこのまま使用しても良い
が、透析、ゲル濾過、遠心分離等の手段によりリ
ポソームに保持されなかつた薬剤を分離除去して
使用しても良い。 In this way, liposome preparations with a uniform particle size holding a drug can be obtained in large quantities with good reproducibility.
This liposome preparation may be used as it is, or it may be used after separating and removing the drug that is not retained in the liposomes by means such as dialysis, gel filtration, or centrifugation.
〈発明の効果〉
既知のリポソーム調製法に比して本発明が優れ
ている点としては先述した他下記の点が挙げられ
る。<Effects of the Invention> In addition to the above-mentioned points, the present invention is superior to known liposome preparation methods in the following points.
１ スケールアツプが容易に可能でありリポソー
ム製剤の工業的製造が可能である。1. Scale-up is easily possible and industrial production of liposome preparations is possible.
２ 噴霧乾燥を用いるので、リポソーム膜成分物
質を損うことがない。2. Since spray drying is used, the liposome membrane component substances are not damaged.
３ 噴霧乾燥によつて得られたリポソーム膜成分
物質、場合によつてはこれと核物質との均質な
混合粉末を粉末形態のまま保存することができ
る。3. The liposome membrane component material obtained by spray drying, and in some cases a homogeneous mixed powder of this and the core material, can be stored in powder form.
４ 薬剤の保持率の高いリポソーム製剤が得られ
る。4. A liposome preparation with high drug retention rate can be obtained.
５ ほとんどすべての脂質を用いてリポソームを
製造することができる。5 Almost any lipid can be used to produce liposomes.
６ 揮発性有機溶媒を回収することができる。6 Volatile organic solvents can be recovered.
次に実施例により本発明を例示するが、これら
の実施例は何ら本発明を限定するものではない。 EXAMPLES Next, the present invention will be illustrated by Examples, but these Examples are not intended to limit the present invention in any way.
参考例
Ｌ−α−ジパルミトイルホスフアチジルコリン
2.94ｇを秤取し、クロロホルム100mlに澄明に溶
解せしめた後、あらかじめ100メツシユ篩下した
Ｄ−マンニトール10.2ｇをこのクロロホルム溶液
中に分散、懸濁せしめた。この懸濁液をスターラ
ーで充分攪拌しながら、噴霧乾燥により溶媒を除
去した。使用した装置は、二流体型の噴霧乾燥装
置（パルビスミニスプレー GA−31型、ヤマト
科学社製）で、噴霧空気圧力は1.0Kg／cm2、送液
速度は約９ｇ／分、チエンバー入口温度は約65
℃、出口温度は約50℃とした。Reference example L-α-dipalmitoylphosphatidylcholine
2.94 g was weighed out and clearly dissolved in 100 ml of chloroform, and then 10.2 g of D-mannitol, which had been passed through a 100 mesh sieve, was dispersed and suspended in the chloroform solution. While thoroughly stirring this suspension with a stirrer, the solvent was removed by spray drying. The equipment used was a two-fluid spray dryer (Parvis Mini Spray GA-31 model, manufactured by Yamato Scientific Co., Ltd.), with a spray air pressure of 1.0 Kg/cm 2 , a liquid feeding rate of approximately 9 g/min, and a chamber inlet temperature. is about 65
℃, and the outlet temperature was approximately 50℃.
得られた均質な白色混合粉末より262.8mgを秤
取し、これにあらかじめ60℃に保温した注射用蒸
留水４mlを加え、充分に膨潤せしめた。温度を50
〜60℃の間に保つたままボルテクスミキサーによ
り充分振とうし、室温に戻したところ、乳白色の
リポソーム懸濁液が得られた。 262.8 mg of the resulting homogeneous white mixed powder was weighed out, and 4 ml of distilled water for injection, which had been kept at 60°C, was added to it to sufficiently swell it. temperature to 50
The mixture was thoroughly shaken using a vortex mixer while being maintained at ~60°C, and when the temperature was returned to room temperature, a milky white liposome suspension was obtained.
このリポソーム懸濁液の粒度分布を準弾性光散
乱計により測定したところ、重量平均として803
±408nmであつた。 When the particle size distribution of this liposome suspension was measured using a quasi-elastic light scattering meter, the weight average was 803.
It was ±408nm.
実施例 １
完全水添精製卵黄レシチン3.2ｇ、コレステロ
ール0.67ｇ及びジセチルホスフエート0.32ｇを秤
取し、クロロホルム100mlに澄明に溶解せしめた
後、あらかじめ100メツシユ篩下したＤ−マンニ
トール10.2ｇをこのクロロホルム溶液中に分散、
懸濁せしめた。参考例と同様にスターラーで攪拌
しながら噴霧乾燥により溶媒を除去し、均質な白
色混合粉末を得た。噴霧乾燥装置、噴霧空気圧
力、送液速度、チエンバー入口温度、出口温度は
参考例と同じにした。Example 1 Weighed out 3.2 g of fully hydrogenated purified egg yolk lecithin, 0.67 g of cholesterol, and 0.32 g of dicetyl phosphate, and dissolved them clearly in 100 ml of chloroform. Dispersed in chloroform solution,
Suspended. As in the reference example, the solvent was removed by spray drying while stirring with a stirrer to obtain a homogeneous white mixed powder. The spray drying device, spray air pressure, liquid feeding rate, chamber inlet temperature, and outlet temperature were the same as in the reference example.
得られた均質な白色混合粉末より141.3mgを秤
取し、これにあらかじめ60℃に保温した0.14Mグ
ルコース水溶液４mlを加え、充分に膨潤せしめ
た。液温50〜60℃の間に保つたままボルテクスミ
キサーにより充分振とうし、室温に戻したとこ
ろ、グルコースを保持した乳白色のリポソーム懸
濁液が得られた。 141.3 mg of the obtained homogeneous white mixed powder was weighed out, and 4 ml of a 0.14M glucose aqueous solution kept at 60° C. was added thereto to sufficiently swell it. When the solution was thoroughly shaken using a vortex mixer while maintaining the solution temperature between 50 and 60° C. and returned to room temperature, a milky white liposome suspension containing glucose was obtained.
このリポソーム懸濁液0.5mlをとり、セロフア
ンチユーブを用いて透析（生理食塩水、１×３
回、５℃）し、リポソームに保持されなかつたグ
ルコースの分離除去した。次いで、リポソーム懸
濁液のグルコースを常法に従つて油／水分配によ
り水層中に抽出し定量したところ、保持率は24.8
％であつた。 Take 0.5 ml of this liposome suspension and dialyze it using cellophane tube (physiological saline, 1 x 3
The glucose not retained in the liposomes was separated and removed. Next, glucose in the liposome suspension was extracted into the aqueous layer by oil/water partitioning according to a conventional method and quantified, and the retention rate was 24.8.
It was %.
実施例 ２
完全水添精製大豆レシチン3.2ｇ、100メツシユ
篩下したＤ−マンニトール10.2ｇ、コレステロー
ル0.67ｇ、ステアリルアミン0.16ｇ及びクロロホ
ルム100mlを用いて実施例１と同様に実施し、均
質な白色混合粉末を得た。噴霧乾燥装置、噴霧空
気圧力、送液速度、チエンバー入口温度、出口温
度は参考例と同じにした。Example 2 The same procedure as in Example 1 was carried out using 3.2 g of fully hydrogenated purified soybean lecithin, 10.2 g of D-mannitol sieved through a 100-mesh sieve, 0.67 g of cholesterol, 0.16 g of stearylamine, and 100 ml of chloroform, resulting in a homogeneous white mixture. A powder was obtained. The spray drying device, spray air pressure, liquid feeding rate, chamber inlet temperature, and outlet temperature were the same as in the reference example.
得られた均質な白色混合粉末より711.5mgを秤
取し、これにあらかじめ60℃に保温した0.14Mグ
ルコース水溶液10mlを加え、以下参考例と同様に
実施したところ、グルコースを保持した乳白色の
リポソーム懸濁液が得られた。 Weighed out 711.5 mg from the homogeneous white mixed powder obtained, added 10 ml of a 0.14 M glucose aqueous solution kept at 60°C, and carried out the same procedure as in the reference example. As a result, a milky white liposome suspension containing glucose was obtained. A cloudy liquid was obtained.
実施例１と同様にしてグルコースの保持率を求
めたところ、24.8％であつた。 When the glucose retention rate was determined in the same manner as in Example 1, it was 24.8%.
実施例 ３
Ｌ−α−ジパルミトイルホスフアチジルコリン
2.94ｇ、コレステロール0.67ｇ及びジセチルホス
フエート0.32ｇを秤取し、クロロホルム100mlに
澄明に溶解せしめた後、あらかじめ100メツシユ
篩下したＤ−ソルビトール10.2ｇをクロロホルム
中に分散、懸濁せしめた。この懸濁液をスターラ
ーで充分攪拌しながら、噴霧乾燥により溶媒を除
去した。噴霧乾燥装置、噴霧空気圧力、送液速
度、チエンバー入口温度、出口温度は実施例１と
同じにした。Example 3 L-α-dipalmitoylphosphatidylcholine
After weighing out 2.94 g of cholesterol, 0.67 g of cholesterol, and 0.32 g of dicetyl phosphate and clearly dissolving them in 100 ml of chloroform, 10.2 g of D-sorbitol, which had been previously sieved through a 100-mesh sieve, was dispersed and suspended in chloroform. While thoroughly stirring this suspension with a stirrer, the solvent was removed by spray drying. The spray drying device, spray air pressure, liquid feeding rate, chamber inlet temperature, and outlet temperature were the same as in Example 1.
得られた均質な白色混合粉末より282.6mgを秤
取し、これにあらかじめ60℃に保温した１％デキ
ストランT40水溶液４mlを用いて、実施例１と同
様に実施したところ、デキストランT40を保持し
た乳白色のリポソーム懸濁液が得られた。このリ
ポソーム懸濁液１mlをとり、セフアロースCL−
4Bを用いてゲル濾過（2.2cmφ×42cm、生理食塩
水）し、リポソームに保持されなかつたデキスト
ランT40を分離除去した。次いで、リポソーム画
分のデキストランT40を常法に従つて油／水分配
により水層中に抽出し定量したところ、保持率は
8.3％であつた。 282.6 mg was weighed out from the obtained homogeneous white mixed powder, and the same procedure as in Example 1 was carried out using 4 ml of a 1% dextran T40 aqueous solution previously kept at 60°C. A liposome suspension was obtained. Take 1 ml of this liposome suspension and add Sepharose CL-
Gel filtration was performed using 4B (2.2 cmφ x 42 cm, physiological saline) to separate and remove dextran T40 that was not retained in the liposomes. Next, dextran T40 from the liposome fraction was extracted into the aqueous layer by oil/water partitioning according to a conventional method and quantified.
It was 8.3%.
実施例 ４
完全水添精製卵黄レシチン32ｇ、コレステロー
ル6.7ｇ及びステアリルアミン1.6ｇを秤取し、ク
ロロホルム500mlに澄明に溶解せしめた後、あら
かじめ100メツシユ篩下したＤ−マンニトール102
ｇをこのクロロホルム溶液中に分散、懸濁せしめ
た。この懸濁液をスターラーで充分攪拌しなが
ら、噴霧乾燥により溶媒を除去した。噴霧乾燥装
置、噴霧空気圧力、送液速度、チエンバー入口温
度、出口温度は参考例と同じにした。Example 4 32 g of fully hydrogenated purified egg yolk lecithin, 6.7 g of cholesterol, and 1.6 g of stearylamine were weighed out and dissolved clearly in 500 ml of chloroform, followed by D-mannitol 102, which had been sieved through a 100-mesh sieve in advance.
g was dispersed and suspended in this chloroform solution. While thoroughly stirring this suspension with a stirrer, the solvent was removed by spray drying. The spray drying device, spray air pressure, liquid feeding rate, chamber inlet temperature, and outlet temperature were the same as in the reference example.
得られた均質な白色混合粉末より35.6mgを秤取
し、これにあらかじめ60℃に保温した0.14Mグル
コース水溶液１を加え、以下アジホモミキサー
を用いて参考例と同様に実施したところ、グルコ
ースを保持した乳白色のリポソーム懸濁液が得ら
れた。実施例１と同様にしてグルコースの保持率
を求めたところ、29.1％であつた。 35.6 mg was weighed out from the obtained homogeneous white mixed powder, 0.14M glucose aqueous solution 1 kept at 60℃ was added thereto, and the following procedure was carried out in the same manner as in the reference example using an Ajihomo mixer. A retained milky liposome suspension was obtained. When the glucose retention rate was determined in the same manner as in Example 1, it was 29.1%.
このリポソーム懸濁液の粒度分布を準弾性光散
乱計により測定したところ、重量平均として768
±512nmであつた。 When the particle size distribution of this liposome suspension was measured using a quasi-elastic light scattering meter, the weight average was 768.
It was ±512nm.
Claims (1)
質、リポソーム膜成分物質及び揮発性有機溶媒か
らなり、リポソーム膜成分物質と揮発性有機溶媒
に不溶で水性溶媒に可溶な物質との重量比が１：
２〜１：2.6の組成物を噴霧乾燥して均一系混合
物を製し、次いで該均一系混合物を水性溶媒中に
分散させることを特徴とするリポソームの製造
法。1 Consists of a substance insoluble in a volatile organic solvent and soluble in an aqueous solvent, a liposome membrane component substance, and a volatile organic solvent, and the weight of the liposome membrane component substance and a substance insoluble in a volatile organic solvent and soluble in an aqueous solvent. The ratio is 1:
A method for producing liposomes, which comprises spray-drying a composition of 2 to 1:2.6 to prepare a homogeneous mixture, and then dispersing the homogeneous mixture in an aqueous solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29568885A JPS62152531A (en) | 1985-12-26 | 1985-12-26 | Preparation of liposome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29568885A JPS62152531A (en) | 1985-12-26 | 1985-12-26 | Preparation of liposome |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62152531A JPS62152531A (en) | 1987-07-07 |
| JPH0437731B2 true JPH0437731B2 (en) | 1992-06-22 |
Family
ID=17823891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29568885A Granted JPS62152531A (en) | 1985-12-26 | 1985-12-26 | Preparation of liposome |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62152531A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5096629A (en) * | 1988-08-29 | 1992-03-17 | 501 Nippon Fine Chemical Co., Ltd. | Method for preparing lipid powder for use in preparing liposomes and method for preparing liposomes |
| JPH02295917A (en) * | 1989-05-10 | 1990-12-06 | Terumo Corp | Liposome suppressing oxidation of internally capsulated substance and production thereof |
| FR2658418B1 (en) * | 1990-02-20 | 1994-09-02 | Synthelabo | PHARMACEUTICAL COMPOSITIONS BASED ON PHOSPHOLIPIDS. |
| AU5533594A (en) * | 1992-11-18 | 1994-06-08 | Taisho Pharmaceutical Co., Ltd. | Stable aqueous liposome suspension |
| EP0982025A1 (en) * | 1998-08-28 | 2000-03-01 | Wilhelm Prof. Dr. Stoffel | Synthetic tear fluid |
| JP2007106679A (en) * | 2005-10-11 | 2007-04-26 | Shino Test Corp | Accelerator for blood coagulation reaction |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5931707A (en) * | 1982-02-17 | 1984-02-20 | パルフユ−ム・クリスチヤン・デイオ−ル | Powdery lipid component and hydrophobic component mixture and manufacture, hydrated lipid layer plate phase and manufacture, medicinal composition or cosmetic composition containing same phase |
| GB2135268A (en) * | 1983-02-15 | 1984-08-30 | Squibb & Sons Inc | Method of preparing liposomes and products produced thereby |
| JPS59173133A (en) * | 1983-02-15 | 1984-10-01 | イ−・ア−ル・スクイブ・アンド・サンズ・インコ−ポレイテツド | Production of liposomes and product |
-
1985
- 1985-12-26 JP JP29568885A patent/JPS62152531A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5931707A (en) * | 1982-02-17 | 1984-02-20 | パルフユ−ム・クリスチヤン・デイオ−ル | Powdery lipid component and hydrophobic component mixture and manufacture, hydrated lipid layer plate phase and manufacture, medicinal composition or cosmetic composition containing same phase |
| GB2135268A (en) * | 1983-02-15 | 1984-08-30 | Squibb & Sons Inc | Method of preparing liposomes and products produced thereby |
| JPS59173133A (en) * | 1983-02-15 | 1984-10-01 | イ−・ア−ル・スクイブ・アンド・サンズ・インコ−ポレイテツド | Production of liposomes and product |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62152531A (en) | 1987-07-07 |
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