WO1997011683A2 - Stabilised phospholipid compositions - Google Patents
Stabilised phospholipid compositions Download PDFInfo
- Publication number
- WO1997011683A2 WO1997011683A2 PCT/GB1996/002364 GB9602364W WO9711683A2 WO 1997011683 A2 WO1997011683 A2 WO 1997011683A2 GB 9602364 W GB9602364 W GB 9602364W WO 9711683 A2 WO9711683 A2 WO 9711683A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- contrast
- nmt
- phosphoiipids
- agent
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 108
- 150000003904 phospholipids Chemical class 0.000 title claims abstract description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007853 buffer solution Substances 0.000 claims abstract description 13
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 7
- 239000000872 buffer Substances 0.000 claims description 43
- 239000002502 liposome Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 29
- 239000007983 Tris buffer Substances 0.000 claims description 19
- 150000002632 lipids Chemical class 0.000 claims description 18
- 239000002872 contrast media Substances 0.000 claims description 17
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 16
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 15
- 239000007995 HEPES buffer Substances 0.000 claims description 14
- 239000002537 cosmetic Substances 0.000 claims description 14
- 230000007935 neutral effect Effects 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 230000001225 therapeutic effect Effects 0.000 claims description 12
- 238000003384 imaging method Methods 0.000 claims description 9
- 239000012736 aqueous medium Substances 0.000 claims description 6
- 230000000069 prophylactic effect Effects 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 5
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 claims description 4
- 230000003019 stabilising effect Effects 0.000 claims description 4
- 238000002604 ultrasonography Methods 0.000 claims description 4
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 2
- 101150035093 AMPD gene Proteins 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims 1
- 239000002907 paramagnetic material Substances 0.000 claims 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 27
- 229960000281 trometamol Drugs 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000007062 hydrolysis Effects 0.000 description 19
- 238000006460 hydrolysis reaction Methods 0.000 description 19
- 235000021588 free fatty acids Nutrition 0.000 description 17
- 239000007994 TES buffer Substances 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 229910019142 PO4 Inorganic materials 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 11
- 238000003860 storage Methods 0.000 description 11
- 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 10
- 230000015556 catabolic process Effects 0.000 description 10
- 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 10
- 238000002360 preparation method Methods 0.000 description 10
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- 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 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 235000013601 eggs Nutrition 0.000 description 9
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- 239000007789 gas Substances 0.000 description 8
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- 150000001875 compounds Chemical class 0.000 description 7
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- 239000007979 citrate buffer Substances 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- -1 phospholipid compounds Chemical class 0.000 description 6
- YFWHNAWEOZTIPI-DIPNUNPCSA-N 1,2-dioctadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCCCC YFWHNAWEOZTIPI-DIPNUNPCSA-N 0.000 description 5
- 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 5
- 102000002322 Egg Proteins Human genes 0.000 description 5
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- 125000004432 carbon atom Chemical group C* 0.000 description 5
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- 210000002969 egg yolk Anatomy 0.000 description 5
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- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 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 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- 239000006185 dispersion Substances 0.000 description 4
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- 229960003194 meglumine Drugs 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
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- 239000000126 substance Substances 0.000 description 4
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 description 3
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 3
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 102000015439 Phospholipases Human genes 0.000 description 3
- 108010064785 Phospholipases Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 125000005518 carboxamido group Chemical group 0.000 description 3
- 239000000032 diagnostic agent Substances 0.000 description 3
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
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- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 3
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- 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
- IBUKXRINTKQBRQ-KCKFLZCVSA-N 1,2-dihexadecanoyl-sn-glycero-3-phospho-D-myo-inositol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O IBUKXRINTKQBRQ-KCKFLZCVSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 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
- KLFKZIQAIPDJCW-HTIIIDOHSA-N Dipalmitoylphosphatidylserine Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCC KLFKZIQAIPDJCW-HTIIIDOHSA-N 0.000 description 2
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- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
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- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- NFRFUGBXJTXTMZ-QYKZUBHNSA-L disodium;[(2r)-2,3-di(hexadecanoyloxy)propyl] phosphate Chemical compound [Na+].[Na+].CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])([O-])=O)OC(=O)CCCCCCCCCCCCCCC NFRFUGBXJTXTMZ-QYKZUBHNSA-L 0.000 description 1
- 238000002593 electrical impedance tomography Methods 0.000 description 1
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- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000002899 fatty ester group Chemical group 0.000 description 1
- 230000005293 ferrimagnetic effect Effects 0.000 description 1
- 239000002902 ferrimagnetic material Substances 0.000 description 1
- 239000003302 ferromagnetic material Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- HZHFFEYYPYZMNU-UHFFFAOYSA-K gadodiamide Chemical compound [Gd+3].CNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NC HZHFFEYYPYZMNU-UHFFFAOYSA-K 0.000 description 1
- 229960005063 gadodiamide Drugs 0.000 description 1
- 229930182830 galactose Natural products 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
- 150000002337 glycosamines Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000000568 immunological adjuvant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960004359 iodixanol Drugs 0.000 description 1
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 1
- 229960001025 iohexol Drugs 0.000 description 1
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- JVKAWJASTRPFQY-UHFFFAOYSA-N n-(2-aminoethyl)hydroxylamine Chemical compound NCCNO JVKAWJASTRPFQY-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- YNQYZBDRJZVSJE-UHFFFAOYSA-M sodium;2,3-dihydroxypropyl 2,3-di(octadecanoyloxy)propyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC YNQYZBDRJZVSJE-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 1
- 229960000909 sulfur hexafluoride Drugs 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000008348 synthetic phosphatidyl choline Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000012285 ultrasound imaging Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0461—Dispersions, colloids, emulsions or suspensions
-
- 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
Definitions
- This invention relates to stabilised aqueous phospholipid compositions.
- Phospholipid compositions are used in a variety of diagnostic, therapeutic and cosmetic applications.
- lipid compositions in particular liposomes, are used to incorporate diagnostic and therapeutic agents, as vehicles for transfer of genetic material, as immunological adjuvants, in preparation of vaccines and in cancer detection.
- diagnostic and therapeutic agents as vehicles for transfer of genetic material, as immunological adjuvants, in preparation of vaccines and in cancer detection.
- the stability of the phospholipid is important for the protection of any entrapped substance from degradation reactions and also for optimum performance of the phospholipid itself.
- Contrast agents are employed to effect imaging enhancement in a variety of diagnostic techniques, the most important of these being X-ray imaging, magnetic resonance imaging (RI) , ultrasound imaging and nuclear medicine imaging. There is a continuing need for contrast agents which combine good storage stability and stability in vivo. Another area of particular interest is the development of stable phospholipid compositions for use in techniques involving autoclavation.
- trometamol and related buffer compounds have a specific effect on the hydrolysis of phosphoiipids. Many of these studies show general acid/base catalysis by the trometamol buffer with increased hydrolysis of the phosphoiipids with increasing concentration of buffer species (see for example Journal of Pharmaceutical Sciences .82 . : 362-366 ( 1993 ) ) .
- the trometamol buffer appeared to provide resistance to hydrolysis and the reference indicates that the reduced oxidation/ hydrolysis observed is due to the fact that trometamol acts as an efficient scavenger of hydroxyl free radicals.
- a similar conclusion is reached in J.Pharm. Pharmacol. 45.: 490-495 (1993) , where a protective effect of buffers such as trometamol against lipid peroxidation is reported.
- WO-95/26205 there are described diagnostic compositions containing multilamellar liposomes containing at least one imaging agent and being suspended in an aqueous medium containing said imaging agent, wherein the liposomes comprise a neutral phospholipid and a charged phospholipid, the average particle diameter of the liposomes is 50-3000 nm and the concentration of imaging agent in any aqueous phase filling the interior of the liposomes is substantially the same as that in the aqueous medium in which the liposomes are suspended.
- substantially saturated phospholipid compounds can be stabilised by buffers, the buffers providing a reduced degree of aqueous hydrolysis of the phosphoiipids.
- the present invention provides an aqueous lipid composition, preferably a liposomal composition and preferably a composition in physiologically tolerable form, comprising one or more substantially saturated phosphoiipids in combination with a buffer system comprising ammonia or a water soluble amine having a pH at 15°C of less than or equal to 9.5, with the proviso that where said phosphoiipids comprise a combination of charged and neutral phosphoiipids and said composition is a liposomal composition containing a nonionic multiply hydroxylated X-ray contrast agent then said agent is not present within the liposomes and within the surrounding aqueous medium at substantially the same concentration.
- a buffer system comprising ammonia or a water soluble amine having a pH at 15°C of less than or equal to 9.5
- a method for stabilising a substantially saturated phospholipid composition comprises including in a substantially saturated phospholipid composition a buffer system comprising ammonia or a water soluble amine having a pH at 15°C of less than or equal to 9.5, other than by adding a said buffer system to a liposomal composition containing a nonionic multiply hydroxylated X-ray contrast agent having said agent present within the liposomes and within the surrounding aqueous medium at substantially the same concentration.
- the buffer may be added before or after liposome generation.
- the invention also provides a method of contrast enhanced imaging in which a contrast medium is administered to a subject (eg. a human or non-human animal, preferably a mammal) and an image of the subject is generated, characterised in that as said contrast medium is used a composition according to the invention containing a contrast effective material.
- a contrast medium may be administered after activation of the contrast effective material, eg. by hyperpolarization.
- the invention provides a method of treatment in which a therapeutic or prophylactic agent is administered to a subject (eg. a human or non-human animal, preferably a mammal) , characterised in that there is administered a composition according to the invention containing a said therapeutic or prophylactic agent.
- a subject eg. a human or non-human animal, preferably a mammal
- the invention provides a method of cosmetic treatment in which a cosmetic agent is administered to a subject (eg. a human or non-human animal, preferably a mammal) characterised in that there is administered a composition according to the invention containing a said cosmetic agent.
- a cosmetic agent eg. a human or non-human animal, preferably a mammal characterised in that there is administered a composition according to the invention containing a said cosmetic agent.
- the compositions administered should contain an effective amount of the active agent (the contrast effective material, the therapeutic or prophylactic agent or the cosmetic agent) , namely an amount sufficient to achieve contrast enhancement or to achieve the desired therapeutic, prophylactic or cosmetic effect.
- the phosphoiipids used in the compositions and methods of the invention may be charged or neutral (ie. carry no net charge) .
- the use of neutral phosphoiipids however is particularly preferred as their protection against hydrolysis by the buffer system is particularly pronounced.
- the phosphoiipids in the compositions of the invention are entirely or substantially entirely neutral phosphoiipids.
- the buffer systems for use in the methods or compositions of the present invention preferably have a pH of 6.0 to 9.5 at room temperature (15°C) , more preferably 6.5 to 8.0, particularly preferably 6.8 to 7.8.
- compositions of the present invention show a reduced degree of hydrolysis of the phospholipid(s) when compared with formulations not including the specified buffer system.
- Preferred compositions according to the present invention show a greater than 5% reduction in the extent of hydrolysis over a given time (eg. a normal shelf life, for example 30 days or more) than occurs with formulations not including the buffer; more preferred compositions show a greater than 10% and most preferably greater than 25% reduction.
- the stabilisation achieved is of especial advantage during storage, during processing and during exposure of the phospholipid compositions to temperature, including during autoclaving.
- the phospholipid compositions are stable at temperatures in the range from 4 to 30°C; in a more preferred embodiment the compositions are stable for temperatures in the range from 4 to 50°C; in another more preferred embodiment the compositions are stable for temperatures in the range of 4 to 125°C (which includes autoclaving) .
- the phospholipid compositions are preferably stable under storage for a period of up to 2 years, more preferably up to 3 years, particularly preferably up to 5 years. "Stable” in this context means that at least 75%, preferably at least 80%, more preferably at least 90%, of undegraded phospholipid is present in the composition after the specified storage period.
- one particular advantage of the stabilization method of the invention is that the resulting phospholipid compositions have the ability to withstand a wide temperature range for a short period. It is preferred, therefore, that for stabilising phospholipid compositions to be autoclaved the buffer system is added prior to autoclaving.
- Buffers which may be employed in the methods or compositions of the present invention are preferably those of formula (I)
- water soluble amines which may be employed as buffers include amino alcohols and amino sugars .
- More preferred amines include trometamol (tris (hydroxymethyl)methylamine, also denoted TRIS) , N,N-bis (2-hydroxyethyl) -tris (hydroxymethyl) methylamine (denoted BIS-TRIS) , 2-amino-2-methylpropane-l, 3-diol (denoted AMPD) , TES, 2- [4- (2-hydroxyethyl) -1- piperazinyl] ethanesulphonic acid (denoted HEPES) , diethanolamine, meglumine, triethanolamine and ammonia.
- TRIS tris (hydroxymethyl)methylamine
- BIS-TRIS N,N-bis (2-hydroxyethyl) -tris (hydroxymethyl) methylamine
- AMPD 2-amino-2-methylpropane-l
- TES 2- [4- (2-hydroxyethyl) -1- pipe
- Especially preferred amines for use according to the invention are TRIS, BIS-TRIS, TES and meglumine in view of their advantageous physiological acceptability and/or advantageous pH values at room temperature.
- the phosphoiipids for inclusion in the compositions of the present invention are, as indicated above, comprised of substantially saturated phosphoiipids.
- substantially saturated means that the fatty acid residues of the phosphoiipids are fully saturated (i.e. contain no C-C double bonds) or that the extent of their unsaturation is very low, e.g. as shown by an iodine value of no more than 10, preferably no more than 5.
- a small proportion of unsaturated phosphoiipids giving an analogous overall extent of unsaturation may also be present in the compositions of the present invention.
- the phosphoiipids may be charged or neutral and may be of natural, synthetic or semi-synthetic origin (including chemically modified substantially saturated phosphoiipids) . As mentioned above the use of neutral phosphoiipids is preferred.
- the number of carbon atoms in the fatty acid residues is usually at least 14, preferably at least 16.
- the number of carbon atoms in the fatty acid residue is also preferably 26 or less, eg. 25 or less, preferably 24 or less.
- Neutral phosphoiipids useful in the present invention include, for example, neutral glycerophospholipids, for example a fully hydrogenated naturally occurring (e.g. soybean- or egg yolk-derived) or synthetic phosphatidylcholine, particularly semisynthetic dipalmitoyl phosphatidylcholine (DPPC) or distearoyl phosphatidylcholine (DSPC) , phosphatidylethanolamine (PE) or phosphatidylethanolamine-polyethyleneglycol (PE- PEG) . More than one neutral phospholipid may be used.
- DPPC dipalmitoyl phosphatidylcholine
- DSPC distearoyl phosphatidylcholine
- PE phosphatidylethanolamine
- PE- PEG phosphatidylethanolamine-polyethyleneglycol
- More than one neutral phospholipid may be used.
- Charged phosphoiipids useful in the present invention include, for example, positively or negatively charged glycerophospholipids.
- Negatively charged phosphoiipids include, for example, phosphatidylserine, for example a fully hydrogenated naturally occurring (e.g. soybean- or egg yolk-derived) or semi-synthetic phosphatidylserine, particularly semi-synthetic dipalmitoyl phosphatidylserine (DPPS) or distearoyl phosphatidylserine (DSPS) - phosphatidylglycerol (PG) , for example fully hydrogenated naturally occurring (e.g.
- DPPS semi-synthetic dipalmitoyl phosphatidylserine
- DSPS distearoyl phosphatidylserine
- PG phosphatidylglycerol
- soybean- or egg yolk-derived soybean- or egg yolk-derived
- semi-synthetic phosphatidylglycerol particularly semi-synthetic or synthetic dipalmitoyl phosphatidylglycerol (DPPG) ; or distearoyl phosphatidylglycerol (DSPG) ; phosphatidylinositol, for example a fully hydrogenated naturally occurring (e.g.
- soybean- or egg yolk-derived or semi-synthetic phosphatidylinositol, particularly semi-synthetic or synthetic dipalmitoyl phosphatidylinositol (DPPI) or distearoyl phosphatidylinositol (DSPI) ; phosphatidic acid, for example a fully hydrogenated naturally occurring (e.g. soybean- or egg yolk-derived) or semi-synthetic phosphatidic acid, particularly semi-synthetic or synthetic dipalmitoyl phosphatidic acid (DPPA) or distearoyl phosphatidic acid (DSPA) .
- DPPI dipalmitoyl phosphatidylinositol
- DSPA distearoyl phosphatidic acid
- Positively charged phosphoiipids include, for example, an ester of phosphatidic acid with an aminoalcohol, such as an ester of dipalmitoyl phosphatidic acid or distearoyl phosphatidic acid with hydroxyethylenediamine. Although such charged phosphoiipids are commonly used alone, more than one charged phospholipid may be used.
- the concentration of the buffer for use in the method of the present invention or in the compositions of the present invention is preferably in the range 2 mM to 200 mM, more preferably 2 mM to 100 mM and particularly preferably 2 mM to 20 mM.
- the molar ratio of buffer:lipid in the compositions of the present invention is preferably in the range 1:60 to 2000:1 (eg. 1:60 to 100:1) , more preferably 1:60 to 1:0.02, particularly preferably 1:60 to 1:0.1.
- Another preferred range of molar ratio of buffer:lipid for some diagnostic and other medical applications is 1:50 to 1:0.1, more preferably 1:20 to 1:0.5, particularly preferably 1:5 to 1:1.
- the concentration of phosphoiipids in the compositions of the present invention for imaging and medical applications is preferably in the range 0.01 mM to 120 mM, eg. 1 mM to 120 mM.
- the phospholipid compositions of the present invention may be in any of the formulation types generally encountered, for example liposomes, emulsions, micelles, microemulsions, lipid particles, lipid solutions and microbubbles. They can be produced by conventional procedures for each particular formulation type.
- the method and the phospholipid compositions of the present invention are suitable for use in a variety of applications and in particular those where increased stability is of especial importance.
- the stabilised compositions can be used in a variety of diagnostic, therapeutic and cosmetic applications and particular mention can be made of phospholipid compositions for use with contrast media (X-ray, MRI , US and scintigraphy) , and for use in cancer therapy, chemotherapy, therapy for fungal infections and treatment of psoriasis.
- the liposomal compositions of the invention will include a contrast-effective material, eg. in the inner cavity of the liposomes, attached to the inner or outer wall of the liposome membrane or contained within the membrane, or in the liquid medium in which the liposomes are dispersed.
- contrast effective it is meant that the material is capable of enhancing contrast in the imaging modality of interest.
- conventional imaging modalities eg. X-ray, MR, ultrasound, magnetotomography, electrical impedance tomography, scintigraphy, SPECT, PET, etc.
- the nature of appropriate contrast effective materials is well known, for example gases (eg.
- the contrast effective material is gaseous (at ambient or body temperature) , eg.
- the contrast effective material is water soluble (eg. a soluble triiodophenyl compound or a paramagnetic metal chelate) it is preferably in solution in the liposome core and especially preferably also in solution in the suspension medium.
- Therapeutic or cosmetic agents may be similarly dispersed within the liposomal core, in or on the liposome membrane and/or in the suspension medium. Conventional therapeutic or cosmetic agents capable of liposomal delivery may be used.
- the concentration of total lipid is generally 5 mg/ml to 100 mg/ml (eg. 20 to 100 mg/ml, conveniently at least 40 or 50 mg/ml) , preferably 10 mg/ml to 90 mg/ml, and more preferably 10 mg/ml to 80 mg/ml, in order to enhance encapsulation of contrast agent in the lipid.
- a preferred range for the concentration of total lipid is generally 0.01 mg/ml to 20 mg/ml, preferably 0.01 mg/ml to 10 mg/ml (eg. 0.5 mg/ml to 10 mg/ml) .
- agents are encapsulated in the phospholipid (particularly in liposomes) this is preferably in the form of an isotonic solution or suspension (relative to physiological osmotic pressure in the body) .
- an isotonic solution or suspension the agent is generally dissolved or suspended in a medium at a concentration which provides an isotonic solution.
- other conventional tonicity adjusters e.g non-toxic water soluble substances
- Such substances include: salts such as sodium chloride,- sugars such as mannitol, glucose, sucrose, mannose, galactose, sorbitol or the like; and polyhydric alcohols such as propylene glycol, glycerine and the like. If sorbitol is employed this is preferably at a concentration of 1 to 500 g/1, more preferably 0.1 to 20 g/lOOml. If glycerine is employed this is preferably at a concentration of 0.05 to 10 g/l00 ml. If the phospholipid compositions are liposomal compositions, the amount of salts used is preferably as small as possible to facilitate stability of the liposomes during storage and autoclaving.
- Isotonic solutions provided by means of the substances mentioned above are also preferably included in those phospholipid compositions according to the present invention which do not incorporate diagnostic, therapeutic or cosmetic agents.
- the present phospholipid compositions may also contain various optional components in addition to the above ⁇ mentioned components.
- vitamin E ⁇ - tocopherol
- vitamin E acetate ester as an antioxidant may be added in an amount of 0.01 to 2 molar %, preferably 0.1 to 1 molar % relative to total amount of lipids.
- Diagnostic, therapeutic and cosmetic agents referred to above may be incorporated into the phospholipid compositions of the present invention by techniques well known in the art.
- the prior art describes the inhibition of phospholipid hydrolysis to be by an indirect mechanism involving inhibition of a phospholipase; such a mechanism clearly does not apply in the present invention since the compositions concerned do not contain phospholipase.
- the reduced oxidation/hydrolysis observed in the prior art using unsaturated phosphoiipids cannot be important in the method of the present invention involving saturated phosphoiipids (not withstanding that traces of unsaturated phosphoiipids can be present) .
- the method of the present invention appears to demonstrate a different inhibition mechanism involving general inhibition of the acid/base catalysed hydrolysis of phospholipid esters.
- composition 1 ml containing:
- the composition was prepared by mixing the lipids with a mixture of chloroform, methanol and water (volume ratio 80:20:0.05) .
- the mixture was heated on a water bath (at 50°C) to dissolve the lipids and the solvents were then removed by heating the solution in a rotary evaporator
- the dispersion was then split into two parts and a buffer of trometamol/HCl having a pH of 7.4 was added to one of the two parts.
- the resulting composition was then filled into vials and autoclaved. Samples were stored at each of 30°, 40° and 50°C for one month. The content of free fatty acids was measured before autoclaving, after autoclaving and after storage.
- FFA free fatty acids
- composition 1 ml containing:
- compositions according to the present invention are prepared as in Example 1 as follows:
- Example 1 As a further Example demonstrating the method of the present invention the following composition (as disclosed in WO-95/26205) was also tested as in Example 1.
- composition 1 ml containing:
- composition was prepared as in Example 1 but additionally adding an isotonic solution of iodixanol and sorbitol prior to the formation of the liposome.
- Examples 8 to 13 below disclose the preparation of stabilized liposome suspensions suitable for use as contrast media in ultrasound (Examples 8 to 10) and magnetic resonance imaging (Examples 11 to 13) investigations. Ratios and percentages are by volume unless otherwise stated, except lipid ratios which are by weight . If 19 F labelled fluorocarbons are used in Examples 8 to 10 these compositions could be used as MR contrast media.
- Hydrogenated egg phosphatidylcholine (HEPC) and dipalmitoylphosphate (10:1) are dissolved m chloroform- methanol (2:1) , and the solvent is then removed in a rotary evaporator.
- the lipids are then dispersed m purified water, and the dispersion is introduced m a gas tight glass reactor equipped with a high speed emulsifier.
- the gas m the reactor is air with 10% C 5 F 12 .
- HEPES 5 mM is added.
- Distearoylphosphatidylcholme DSPC
- dipalmitoylphosphatidic acid DPPA
- polyethyleneglycol PEG 4000
- the lipids are then dispersed in purified water, and the dispersion is introduced in a gas tight glass reactor equipped with a high speed emulsifier.
- the gas in the reactor is C 3 F 8 .
- trometamol 8mM is added.
- Dipalmitoylphosphatidylcholme (DPPC) , dipalmitoylphosphatidic acid (DPPA) and dipalmitoylphosphatidylethanolamine (DPPE) (8:1:1) are dissolved in chloroform-methanol-water (10:20:0.5), and the solvent is then removed in a rotary evaporator.
- the lipids are then dispersed in purified water, and the dispersion is introduced in a gas tight glass reactor equipped with a high speed emulsifier.
- the gas in the reactor is C 4 H 10 .
- TES 10 mM is added.
- Hydrogenated egg phosphatidylcholine (HEPC) and methoxy(PEG) -distearoylphosphatidylethanolamine (MPEG- DSPE) (9:1) are dry blended and dispersed in gadodiamide-caldiamide 0.5 M solution. Liposomes are then prepared by homogenisation and extrusion. HEPES 8 mM is added and the product is sterilised by autoclaving.
- HEPC Hydrogenated egg phosphatidylcholine
- MPEG- DSPE methoxy(PEG) -distearoylphosphatidylethanolamine
- Hydrogenated egg phosphatidylcholine (HEPC) and dipalmitoylphosphatidylglycerol (DPPG) (9:1) are dry blended and dispersed in dimegluminegadopentetate- meglumine diethylenetriaminepentetate-meglumine 0.5 M solution. Liposomes are then prepared by homogenisation and extrusion. TRIS 50 mM is added and the product is sterilised by autoclaving.
- Hydrogenated egg phosphatidylcholine (HEPC) is dispersed in gadodiamide 0.5 M solution. Liposomes are then prepared by homogenisation and extrusion. TES 50 mM is added and the product is sterilised by autoclaving.
- HEPC Hydrogenated egg phosphatidylcholine
- compositions were prepared, as in Example 1, using TRIS, HEPES or TES buffers.
- TES is 1- [tris (hydroxymethyl)methyl] -2-aminoethane sulphonic acid.
- compositions were prepared for comparison.
- the buffer was TRIS, HEPES or TES
- a second no buffer was used with pH being adjusted with NaOH/HCl
- a third phosphate buffer or phosphate/citrate buffer was used.
- the compositions were prepared as in Example 1.
- Degradation of the phospholipid, measured as free fatty acids (mg/mL) after autoclaving and after 3 months storage at 40°C was as follows: Buffer After autoclaving 3 months, 40°C
- samples with TRIS and TRIS- like buffers show less degradation of the phospholipid as seen by the reduced level of free fatty acids compared with other buffers (phosphate buffer and phosphate/citrate buffer) and solutions without buffer (pH adjusted by NaOH/HCl) .
- the reduction in pH observed after autoclaving and storage was less pronounced in the samples with TRIS, HEPES and TES (a reduction of less than 0.30 pH units) compared with the other samples (a reduction of 0.30-1.00 pH units) .
- Example 16 Composition:
- the buffer was TRIS, HEPES or TES
- a second no buffer was used with pH being adjusted with NaOH/HCl
- a third phosphate buffer or phosphate/citrate buffer was used.
- the compositions were prepared as in Example 1.
- Degradation of the phospholipid, measured as free fatty acids (mg/mL) after autoclaving and after 1 month's storage at 40°C and 50°C was as follows: Buffer After autoclaving 1 month 40°C 1 month 50°C
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96931893A EP0857070A2 (en) | 1995-09-27 | 1996-09-25 | Stabilised phospholipid compositions |
JP09513213A JP2000515487A (en) | 1995-09-27 | 1996-09-25 | Stabilized phospholipid composition |
NO981340A NO981340D0 (en) | 1995-09-27 | 1998-03-24 | Stabilized phospholipid compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9519654.9 | 1995-09-27 | ||
GBGB9519654.9A GB9519654D0 (en) | 1995-09-27 | 1995-09-27 | Stabilised phospholipid compositions |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09043575 A-371-Of-International | 1998-07-13 | ||
US09/982,196 Continuation US20020039556A1 (en) | 1995-09-27 | 2001-10-19 | Stabilised phospholipid compositions |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1997011683A2 true WO1997011683A2 (en) | 1997-04-03 |
WO1997011683A3 WO1997011683A3 (en) | 1997-06-26 |
Family
ID=10781317
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1996/002364 WO1997011683A2 (en) | 1995-09-27 | 1996-09-25 | Stabilised phospholipid compositions |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0857070A2 (en) |
JP (1) | JP2000515487A (en) |
CN (1) | CN1202830A (en) |
CA (1) | CA2233135A1 (en) |
GB (1) | GB9519654D0 (en) |
NO (1) | NO981340D0 (en) |
WO (1) | WO1997011683A2 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002114711A (en) * | 2000-10-12 | 2002-04-16 | Lion Corp | External preparation composition |
WO2007129311A3 (en) * | 2006-05-04 | 2008-01-31 | Pan Sci Tech S A | Nano-particles with contrast agents for diagnostic delivery system for x-ray and ct |
JP2011105764A (en) * | 2011-02-23 | 2011-06-02 | Lion Corp | External preparation composition |
WO2020127992A1 (en) * | 2018-12-21 | 2020-06-25 | Ge Healthcare As | Ultrasound contrast agent and methods for use thereof |
WO2024199424A1 (en) * | 2023-03-30 | 2024-10-03 | 上海济煜医药科技有限公司 | Phospholipid composition, preparation method therefor and use of nitrogen-containing compound |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0821158A2 (en) * | 2007-12-20 | 2015-06-16 | Novartis Ag | Method for Making Contact Lenses |
CN104561156B (en) * | 2013-10-28 | 2020-07-07 | 丰益(上海)生物技术研发中心有限公司 | Process for preparing saturated phospholipids |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE60901B1 (en) * | 1986-08-21 | 1994-08-24 | Vestar Inc | Improved treatment of systemic fungal infections with phospholipid particles encapsulating polyene antifungal antibiotics |
US4962022A (en) * | 1986-09-22 | 1990-10-09 | Becton Dickinson And Company | Storage and use of liposomes |
ZA902710B (en) * | 1989-05-22 | 1991-12-24 | Univ Georgia Res Found | Enzyme luminescence assay |
DE69527194T2 (en) * | 1994-03-28 | 2003-02-06 | Daiichi Pharmaceutical Co., Ltd. | LIPOSOME CONTAINING AN X-RAY OR ULTRASONIC CONTRAST |
-
1995
- 1995-09-27 GB GBGB9519654.9A patent/GB9519654D0/en active Pending
-
1996
- 1996-09-25 EP EP96931893A patent/EP0857070A2/en not_active Withdrawn
- 1996-09-25 JP JP09513213A patent/JP2000515487A/en active Pending
- 1996-09-25 CN CN96198585A patent/CN1202830A/en active Pending
- 1996-09-25 CA CA002233135A patent/CA2233135A1/en not_active Abandoned
- 1996-09-25 WO PCT/GB1996/002364 patent/WO1997011683A2/en not_active Application Discontinuation
-
1998
- 1998-03-24 NO NO981340A patent/NO981340D0/en not_active Application Discontinuation
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002114711A (en) * | 2000-10-12 | 2002-04-16 | Lion Corp | External preparation composition |
WO2007129311A3 (en) * | 2006-05-04 | 2008-01-31 | Pan Sci Tech S A | Nano-particles with contrast agents for diagnostic delivery system for x-ray and ct |
JP2011105764A (en) * | 2011-02-23 | 2011-06-02 | Lion Corp | External preparation composition |
WO2020127992A1 (en) * | 2018-12-21 | 2020-06-25 | Ge Healthcare As | Ultrasound contrast agent and methods for use thereof |
US20220096666A1 (en) * | 2018-12-21 | 2022-03-31 | Ge Healthcare As | Ultrasound contrast agent and methods for use thereof |
WO2024199424A1 (en) * | 2023-03-30 | 2024-10-03 | 上海济煜医药科技有限公司 | Phospholipid composition, preparation method therefor and use of nitrogen-containing compound |
Also Published As
Publication number | Publication date |
---|---|
WO1997011683A3 (en) | 1997-06-26 |
NO981340L (en) | 1998-03-24 |
NO981340D0 (en) | 1998-03-24 |
CA2233135A1 (en) | 1997-04-03 |
JP2000515487A (en) | 2000-11-21 |
CN1202830A (en) | 1998-12-23 |
EP0857070A2 (en) | 1998-08-12 |
GB9519654D0 (en) | 1995-11-29 |
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