JPH06192066A - Stable liposome aqueous suspension - Google Patents
Stable liposome aqueous suspensionInfo
- Publication number
- JPH06192066A JPH06192066A JP5263952A JP26395293A JPH06192066A JP H06192066 A JPH06192066 A JP H06192066A JP 5263952 A JP5263952 A JP 5263952A JP 26395293 A JP26395293 A JP 26395293A JP H06192066 A JPH06192066 A JP H06192066A
- Authority
- JP
- Japan
- Prior art keywords
- aqueous suspension
- liposome
- liposome aqueous
- aminocaproic acid
- epsilon
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 37
- 239000007900 aqueous suspension Substances 0.000 title claims abstract description 25
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229960002684 aminocaproic acid Drugs 0.000 claims abstract description 19
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 6
- 229960000686 benzalkonium chloride Drugs 0.000 claims abstract description 5
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 claims abstract description 5
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002245 particle Substances 0.000 abstract description 8
- 229960003080 taurine Drugs 0.000 abstract description 5
- 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 abstract description 4
- 229930195725 Mannitol Natural products 0.000 abstract description 4
- 150000001413 amino acids Chemical class 0.000 abstract description 4
- 239000000594 mannitol Substances 0.000 abstract description 4
- 235000010355 mannitol Nutrition 0.000 abstract description 4
- 238000013329 compounding Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 230000002949 hemolytic effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000001556 precipitation Methods 0.000 abstract description 2
- 230000015271 coagulation Effects 0.000 abstract 1
- 238000005345 coagulation Methods 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 239000012528 membrane Substances 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class 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 5
- 229940099578 hydrogenated soybean lecithin Drugs 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000004417 polycarbonate Substances 0.000 description 5
- 229920000515 polycarbonate Polymers 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 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 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- FVJZSBGHRPJMMA-IOLBBIBUSA-N PG(18:0/18:0) Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-IOLBBIBUSA-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
- -1 activated B 2 Chemical compound 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 238000011085 pressure filtration Methods 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229940042585 tocopherol acetate Drugs 0.000 description 2
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical class CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 1
- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 description 1
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 1
- 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 1
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-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
- 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 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930003427 Vitamin E Natural products 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
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 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 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 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
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229960003517 isothipendyl Drugs 0.000 description 1
- OQJBSDFFQWMKBQ-UHFFFAOYSA-N isothipendyl Chemical compound C1=CN=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 OQJBSDFFQWMKBQ-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明はリポソームを水性懸濁液
の状態で保存してもリポソームを安定に保存できる技術
に関する。FIELD OF THE INVENTION The present invention relates to a technique for stably storing liposomes even when the liposomes are stored in an aqueous suspension state.
【０００２】[0002]
【従来の技術】リポソームは脂質二分子膜よりなる閉鎖
小胞であり、生体適合性に優れているためその内水相ま
たは膜中に、種々の薬物を保持させてドラッグキャリア
ーとして用いる試みが数多くなされている。しかしなが
らリポソームは水溶液の状態ではコロイド化学的に不安
定な場合が多く、リポソーム粒子同士の凝集や融合、膜
成分の結晶化による沈澱の生成、粒子径の増大などがお
こり、効力及び外観変化による商品価値の損失となりや
すかった。そのため、水性懸濁液タイプではなく凍結乾
燥等の手段により用時溶解タイプが考えられており、リ
ポソームの水性懸濁液の安定化は検討例が少なく、その
方法として多価アルコール及びまたは糖類を配合して安
定化させる方法が報告されている（特開昭６４−３１１
４）。また、アミノ酸を用いてリポソームを安定化する
特開昭６２−４２７３３号公報記載の技術がある。2. Description of the Related Art Liposomes are closed vesicles composed of lipid bilayers, and because of their excellent biocompatibility, many attempts have been made to retain various drugs in their internal aqueous phase or membranes and use them as drug carriers. Has been done. However, liposomes are often colloidally unstable in the state of aqueous solution, causing aggregation and fusion of liposome particles, formation of precipitate due to crystallization of membrane components, increase in particle size, etc. It was easy to lose value. Therefore, a type such as freeze-drying is considered to be a type that dissolves before use by means such as freeze-drying, and there are few studies on stabilization of the aqueous suspension of liposomes. A method of compounding and stabilizing has been reported (JP-A-64-311).
4). Further, there is a technique described in JP-A-62-42733, which stabilizes a liposome using an amino acid.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、上記技
術で解決したのは室温以下の保存温度での安定性であ
り、高温に保存された時の安定化や、溶血性があるとい
われているリゾ体の生成抑制については不十分であっ
た。本発明の目的は、４０℃の保存でも６ヶ月間、沈澱
や凝集、粒子径変化がなく，またリゾ体の生成も少ない
安定なリポソーム水性懸濁液を提供することにある。However, what has been solved by the above technique is the stability at storage temperatures below room temperature, which is said to be stable when stored at high temperatures and which is said to have hemolytic properties. Inhibition of body formation was insufficient. It is an object of the present invention to provide a stable liposome aqueous suspension that does not undergo precipitation or aggregation or change in particle size for 6 months even when stored at 40 ° C. and has less lyso form.
【０００４】[0004]
【課題を解決するための手段】本発明者らは鋭意研究し
た結果、アミノ酸の一種であるイプシロンアミノカプロ
ン酸をリポソーム水性懸濁液に配合すると、他のアミノ
酸やその他の物質では解決できなかった上記課題を解決
できることを見いだし、本発明を完成した。すなわち、
本発明はイプシロンアミノカプロン酸を配合したことを
特徴とするリポソーム水性懸濁液である。Means for Solving the Problems As a result of intensive studies conducted by the present inventors, when epsilon aminocaproic acid, which is one of the amino acids, was added to a liposome aqueous suspension, other amino acids and other substances could not solve the above problems. The inventors have found that the problems can be solved and completed the present invention. That is,
The present invention is a liposome aqueous suspension containing epsilon aminocaproic acid.
【０００５】本発明において、イプシロンアミノカプロ
ン酸の配合量は製剤全量に対して０．５〜５．０重量％
であり、好ましくは１．０〜３．０重量％である。ま
た、本発明においては、イプシロンアミノカプロン酸と
共に塩化ベンザルコニウム、塩化ベンゼトニウムなどの
第４級アンモニウム塩（好ましくは塩化ベンザルコニウ
ム）をリポソーム水性懸濁液に配合するとより優れた効
果が得られて好ましく、さらにタウリン及び／またはマ
ンニトールを併せて配合すると好ましい。ここで、前記
第４級アンモニウム塩の配合量はリポソームの膜成分
（後述）に対して０．０５〜２０モル％、好ましくは２
〜８モル％である。また、前記タウリンの配合量は、
０．５〜３．０重量％である。前記マンニトールは、リ
ポソームの分散安定性を損なわない量を加えることがで
きる。In the present invention, the content of epsilon aminocaproic acid is 0.5 to 5.0% by weight based on the total amount of the preparation.
And preferably 1.0 to 3.0% by weight. Further, in the present invention, when a quaternary ammonium salt (preferably benzalkonium chloride) such as benzalkonium chloride or benzethonium chloride is mixed with epsilon aminocaproic acid in a liposome aqueous suspension, a more excellent effect can be obtained. It is preferable that taurine and / or mannitol be further added together. Here, the compounding amount of the quaternary ammonium salt is 0.05 to 20 mol% with respect to the membrane component of the liposome (described later), preferably 2
~ 8 mol%. In addition, the amount of the taurine compounded is
It is 0.5 to 3.0% by weight. The mannitol can be added in an amount that does not impair the dispersion stability of the liposome.
【０００６】本発明のリポソーム水性懸濁液は例えば次
にようにして調製することができる。すなわちリポソー
ムの膜成分を有機溶媒に溶解し、有機溶媒を留去した
後、生成した脂質膜を、イプシロンアミノカプロン酸
（並びに好ましくはタウリン、第４級アンモニウム塩、
酸性燐脂質及び／またはマンニトール）含有水溶液で水
和すればよいが、特にこの方法に限定されるわけではな
い。上記膜成分としては水素添加大豆レシチン、水素添
加卵黄レシチン、ジミリストイルフォスファチジルコリ
ン、ジパルミトイルフォスファチジルコリン、ジステア
ロイルフォスファチジルコリン、ホスファチジルエタノ
ールアミン、スフィンゴミエリン、フォスファチジルグ
リセロール、フォスファチジン酸、フォスファチジルセ
リン、カルジオリピンなどを挙げることができる。膜安
定化剤は特に必要ないがコレステロール等を入れても構
わない。これらの膜成分の使用量は、通常水１重量部に
対し０.０００５〜０.０２５重量部好ましくは０.００
１〜０.００８重量部である。 また、有機溶媒として
はクロロホルム、ジクロルメタンなどを用いることがで
きる。The liposome aqueous suspension of the present invention can be prepared, for example, as follows. That is, after dissolving the membrane component of the liposome in an organic solvent and distilling off the organic solvent, the produced lipid membrane is treated with epsilon aminocaproic acid (and preferably taurine, a quaternary ammonium salt,
It may be hydrated with an aqueous solution containing acidic phospholipid and / or mannitol, but is not particularly limited to this method. As the membrane component, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, sphingomyelin, phosphatidylglycerol, phospha Tizic acid, phosphatidylserine, cardiolipin and the like can be mentioned. A membrane stabilizer is not particularly required, but cholesterol or the like may be added. The amount of these membrane components used is usually 0.0005 to 0.025 parts by weight, preferably 0.00, relative to 1 part by weight of water.
1 to 0.008 parts by weight. Further, as the organic solvent, chloroform, dichloromethane or the like can be used.
【０００７】本発明においてはリポソームの水性懸濁液
のｐＨを水酸化ナトリウム、水酸化カリウム等で中性付
近（６.０〜７.４）に調整することが望ましい。また、
本発明においては必要に応じてポリカーボネート製メン
ブランフィルターや高圧噴射型ホモジナイザーを用いて
粒径分布をコントロールしてもよい。In the present invention, it is desirable that the pH of the aqueous suspension of liposomes is adjusted to near neutral (6.0 to 7.4) with sodium hydroxide, potassium hydroxide or the like. Also,
In the present invention, a particle size distribution may be controlled by using a polycarbonate membrane filter or a high-pressure injection type homogenizer, if necessary.
【０００８】本発明のリポソーム懸濁液には必要に応じ
て防腐剤（例えばパラオキシ安息香酸メチル、パラオキ
シ安息香酸エチル、パラオキシ安息香酸プロピルな
ど）、抗ヒスタミン剤（例えば塩酸ジフェンヒドラジ
ン、塩酸イソチペンジル、マレイン酸クロルフェニラミ
ンなど）、ビタミン類（例えばビタミンＡ及びそのエス
テル、活性型Ｂ2、ビタミンＢ2、ビタミンＢ6、ビタミ
ンＢ12、ビタミンＥ及びそのエステルなど）、高分子添
加剤（例えばポリエチレングリコール、ポリビニルアル
コール、ポリビニルピロリドン、ヒドロキシエチルセル
ロース、ヒドロキシプロピルメチルセルロースなど）、
等張化剤（例えば塩化ナトリウム、塩化カリウムなど）
などを本発明の効果を損なわない範囲内で添加してもよ
い。The liposome suspension of the present invention may optionally contain a preservative (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, etc.), an antihistamine (eg, diphenhydrazine hydrochloride, isothipendyl hydrochloride, maleic acid). Chlorpheniramine, etc.), vitamins (eg vitamin A and its esters, activated B 2 , vitamin B 2 , vitamin B 6 , vitamin B 12 , vitamin E and its esters, etc.), polymeric additives (eg polyethylene glycol, Polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, etc.),
Isotonic agents (eg sodium chloride, potassium chloride, etc.)
Etc. may be added within a range that does not impair the effects of the present invention.
【０００９】本発明のリポソーム水性懸濁液に保持させ
る薬物としては特に制限はなく、水溶性薬物の場合は薬
物をイプシロンアミノカプロン酸含有水溶液に溶解して
脂質膜に加え、水和させればよく、油溶性薬物の場合は
薬物と膜成分とをクロロホルムなどの溶媒に溶解し、溶
媒を留去した後、イプシロンアミノカプロン酸含有水溶
液で水和すればよい。The drug to be held in the liposome aqueous suspension of the present invention is not particularly limited, and in the case of a water-soluble drug, the drug may be dissolved in an aqueous solution containing epsilon aminocaproic acid, added to the lipid membrane and hydrated. In the case of an oil-soluble drug, the drug and the membrane component may be dissolved in a solvent such as chloroform, and the solvent may be distilled off, followed by hydration with an aqueous solution containing epsilon aminocaproic acid.
【００１０】[0010]
【発明の効果】本発明により，ｐＨ変動が少なく高温保
存でも長期間安定で，かつリポソームが加水分解してリ
ゾ体を生じることの少ないリポソーム水性懸濁液を提供
することが可能となった。Industrial Applicability According to the present invention, it is possible to provide a liposome aqueous suspension which has a small pH fluctuation, is stable for a long period of time even at high temperature storage, and is less likely to hydrolyze a liposome to form a lyso form.
【００１１】[0011]
【実施例】以下、実施例及び試験例を挙げて、本発明を
更に詳細に説明する。 実施例１ 水素添加大豆レシチン２００ｍｇと脂溶性の薬物である
ビタミンＥアセテート５０ｍｇをナスフラスコにとりク
ロロホルム５０ｍｌに溶解した後クロロホルムを充分に
留去した。これに水酸化ナトリウムでｐＨを６．５に調
整した３％イプシロンアミノカプロン酸水溶液を１０ｍ
ｌ加え、６０〜７０℃で水和した後、０．２μｍのポリ
カーボネート製メンブランで１回，０．１μｍのポリカ
ーボネート製メンブランで１回加圧濾過によるサイジン
グを行った。このうち、５ｍｌをとり、塩化ベンザルコ
ニウムを最終的に０．００５％（Ｗ／Ｖ）（膜成分に対
して５モル％）となるように加え、更にｐＨ６．５の３
％イプシロンアミノカプロン酸水溶液を加えて、全量５
０ｍｌのリポソーム水性懸濁液を調製した。EXAMPLES The present invention will be described in more detail below with reference to examples and test examples. Example 1 200 mg of hydrogenated soybean lecithin and 50 mg of vitamin E acetate, which is a fat-soluble drug, were placed in an eggplant-shaped flask and dissolved in 50 ml of chloroform, and then chloroform was sufficiently distilled off. 10m of a 3% aqueous solution of epsilon aminocaproic acid whose pH was adjusted to 6.5 with sodium hydroxide.
After hydration at 60 to 70 ° C., sizing was performed by pressure filtration once with a 0.2 μm polycarbonate membrane and once with a 0.1 μm polycarbonate membrane. Of this, 5 ml was taken, benzalkonium chloride was added so that the final concentration was 0.005% (W / V) (5 mol% based on the membrane components), and the pH was adjusted to 3 at pH 6.5.
% Epsilon aminocaproic acid aqueous solution is added to bring the total amount to 5
0 ml of liposome aqueous suspension was prepared.
【００１２】実施例２ 膜成分として水素添加大豆レシチン２００ｍｇの代わり
にジステアロイリルフォスファチジルコリン２００ｍｇ
を用い、ｐＨ６．５の３％イプシロンアミノカプロン酸
水溶液の代わりにｐＨ６．５の２％イプシロンアミノカ
プロン酸と１％タウリンの混合水溶液を用いた他は実施
例１と同様にしてリポソーム水性懸濁液を調製した。た
だし、水和とサイシングは５０〜６０℃で行った。Example 2 Instead of hydrogenated soybean lecithin 200 mg as a membrane component, distearoylylphosphatidylcholine 200 mg
Was used, and a liposome aqueous suspension was prepared in the same manner as in Example 1 except that a mixed aqueous solution of 2% epsilon aminocaproic acid and 1% taurine at pH 6.5 was used in place of the 3% epsilon aminocaproic acid aqueous solution at pH 6.5. Prepared. However, hydration and sicing were performed at 50 to 60 ° C.
【００１３】実施例３ 水素添加大豆レシチン２００ｍｇとジステアロイルフォ
スファチジルグリセロール２０ｍｇ，脂溶性の薬物であ
るビタミンＥアセテート５０ｍｇをナスフラスコにとり
クロロホルム５０ｍｌに溶解した後クロロホルムを充分
に留去した。これに水酸化ナトリウムでｐＨを６．５に
調整した３％イプシロンアミノカプロン酸水溶液を１０
ｍｌ加え、６０〜７０℃で水和した後、０．２μｍのポ
リカーボネート製メンブランで１回，０．１μｍのポリ
カーボネート製メンブランで１回加圧濾過によるサイジ
ングを行った。更にｐＨ６．５の３％イプシロンアミノ
カプロン酸水溶液を加えて、全量５０ｍｌのリポソーム
水性懸濁液を調製した。Example 3 200 mg of hydrogenated soybean lecithin, 20 mg of distearoylphosphatidylglycerol and 50 mg of the fat-soluble drug vitamin E acetate were placed in an eggplant-shaped flask and dissolved in 50 ml of chloroform, and chloroform was distilled off sufficiently. To this, 10% 3% epsilon aminocaproic acid aqueous solution adjusted to pH 6.5 with sodium hydroxide was added.
After adding ml and hydrating at 60 to 70 ° C., sizing was performed by pressure filtration once with a 0.2 μm polycarbonate membrane and once with a 0.1 μm polycarbonate membrane. Furthermore, a 3% epsilon aminocaproic acid aqueous solution having a pH of 6.5 was added to prepare a liposome aqueous suspension having a total volume of 50 ml.
【００１４】実施例４ 膜成分として水素添加大豆レシチン１５０ｍｇ、ジステ
アロイルフォスファチジルグリセロール２０ｍｇ及びコ
レステロール５０ｍｇを用いた他は実施例３と同様にし
てリポソーム水性懸濁液を調製した。Example 4 A liposome aqueous suspension was prepared in the same manner as in Example 3 except that 150 mg of hydrogenated soybean lecithin, 20 mg of distearoylphosphatidylglycerol and 50 mg of cholesterol were used as membrane components.
【００１５】対照例１ 実施例１において，３％イプシロンアミノカプロン酸水
溶液の代わりに２．３％グリセリン水溶液を用いた他は
実施例１と同様にしてリポソーム水性懸濁液を調製し
た。Control Example 1 A liposome aqueous suspension was prepared in the same manner as in Example 1 except that a 2.3% glycerin aqueous solution was used in place of the 3% epsilon aminocaproic acid aqueous solution.
【００１６】対照例２ 実施例１において，３％イプシロンアミノカプロン酸水
溶液の代わりに生理食塩水を用いたほかは実施例１と同
様にしてリポソーム水性懸濁液を調製した。Control Example 2 A liposome aqueous suspension was prepared in the same manner as in Example 1 except that physiological saline was used in place of the 3% epsilon aminocaproic acid aqueous solution.
【００１７】試験例１ 実施例１、対照例１及び対照例２のリポソーム水性懸濁
液を２ｍｌ透明アンプルに入れ、６５℃及び４０℃で保
存し、経時的に薄層クロマトグラフィー（ＴＬＣ）によ
りフォスファチジルコリンを分離し、この部分をかき取
ってリンの定量を行いフォスファチジルコリンの含量を
測定した。その結果を表１に示す。主な分解生成物であ
るリゾ体の生成は実施例１のほうが対照例１及び対照例
２よりも少なくリポソームは安定であった。Test Example 1 The liposome aqueous suspensions of Example 1, Control Example 1 and Control Example 2 were placed in a 2 ml transparent ampoule, stored at 65 ° C. and 40 ° C., and subjected to thin layer chromatography (TLC) over time. Phosphatidylcholine was separated, and this portion was scraped off to quantify phosphorus to determine the content of phosphatidylcholine. The results are shown in Table 1. The production of lyso form, which is a main decomposition product, was smaller in Example 1 than in Control Example 1 and Control Example 2, and the liposome was stable.
【００１８】[0018]
【表１】 [Table 1]
【００１９】試験例２ 実施例１、対照例１及び対照例２のリポソーム水性懸濁
液をアンプルに入れ４０℃に保存し、外観変化を観察
し、粒径を測定した。その結果を表２に示す。実施例１
は凝集や粒径の変化も認められなかったが、対照例１及
び対照例２の場合は実施例１の場合に比べ、凝集も多く
粒径も大きくなった。Test Example 2 The liposome aqueous suspensions of Example 1, Control Example 1 and Control Example 2 were placed in an ampoule and stored at 40 ° C., the appearance change was observed, and the particle size was measured. The results are shown in Table 2. Example 1
No aggregation or change in particle size was observed, but in Comparative Examples 1 and 2, there was more aggregation and larger particle size than in Example 1.
【００２０】[0020]
【表２】 [Table 2]
【００２１】[0021]
───────────────────────────────────────────────────── フロントページの続き (72)発明者 中島 俊明 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 小田原 美樹子 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Toshiaki Nakajima 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Mikiko Odawara 3-24-1 Takada, Toshima-ku, Tokyo Taisho Inside Pharmaceutical Co., Ltd.
Claims (3)
リポソーム水性懸濁液。1. A liposome aqueous suspension containing epsilon aminocaproic acid.
アンモニウム塩を配合したリポソーム水性懸濁液。2. A liposome aqueous suspension containing epsilon aminocaproic acid and a quaternary ammonium salt.
ニウムである、請求項２記載のリポソーム水性懸濁液。3. The liposome aqueous suspension according to claim 2, wherein the quaternary ammonium salt is benzalkonium chloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5263952A JPH06192066A (en) | 1992-10-27 | 1993-10-22 | Stable liposome aqueous suspension |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28859692 | 1992-10-27 | ||
| JP4-288596 | 1992-10-27 | ||
| JP5263952A JPH06192066A (en) | 1992-10-27 | 1993-10-22 | Stable liposome aqueous suspension |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06192066A true JPH06192066A (en) | 1994-07-12 |
Family
ID=26546276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5263952A Pending JPH06192066A (en) | 1992-10-27 | 1993-10-22 | Stable liposome aqueous suspension |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06192066A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5720948A (en) * | 1995-11-07 | 1998-02-24 | Helene Curtis Inc. | Non-ionic surfactant emulsion vehicles and their use for deposition of drug into and across skin |
-
1993
- 1993-10-22 JP JP5263952A patent/JPH06192066A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5720948A (en) * | 1995-11-07 | 1998-02-24 | Helene Curtis Inc. | Non-ionic surfactant emulsion vehicles and their use for deposition of drug into and across skin |
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