CN1098068C - 装有用于诊断和治疗的多相组合物的容器 - Google Patents
装有用于诊断和治疗的多相组合物的容器 Download PDFInfo
- Publication number
- CN1098068C CN1098068C CN95195094A CN95195094A CN1098068C CN 1098068 C CN1098068 C CN 1098068C CN 95195094 A CN95195094 A CN 95195094A CN 95195094 A CN95195094 A CN 95195094A CN 1098068 C CN1098068 C CN 1098068C
- Authority
- CN
- China
- Prior art keywords
- gas
- liposome
- container
- sealing
- filled
- 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
- 230000001225 therapeutic effect Effects 0.000 title abstract description 3
- 239000000203 mixture Substances 0.000 title description 35
- 239000012071 phase Substances 0.000 claims abstract description 23
- 239000007789 gas Substances 0.000 claims description 309
- 239000002502 liposome Substances 0.000 claims description 182
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 50
- -1 palmityl phosphatidic acid Chemical compound 0.000 claims description 45
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 claims description 44
- 229960004065 perflutren Drugs 0.000 claims description 44
- 239000003570 air Substances 0.000 claims description 37
- 238000011049 filling Methods 0.000 claims description 37
- 239000002872 contrast media Substances 0.000 claims description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 29
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 239000007788 liquid Substances 0.000 claims description 26
- 239000007791 liquid phase Substances 0.000 claims description 21
- 239000007900 aqueous suspension Substances 0.000 claims description 20
- 239000000232 Lipid Bilayer Substances 0.000 claims description 18
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 18
- 238000007789 sealing Methods 0.000 claims description 18
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 17
- 229910018503 SF6 Inorganic materials 0.000 claims description 17
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical group FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 claims description 17
- 229960000909 sulfur hexafluoride Drugs 0.000 claims description 17
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- NJCBUSHGCBERSK-UHFFFAOYSA-N perfluoropentane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F NJCBUSHGCBERSK-UHFFFAOYSA-N 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 claims description 14
- 230000005298 paramagnetic effect Effects 0.000 claims description 14
- 229960004692 perflenapent Drugs 0.000 claims description 14
- 239000010410 layer Substances 0.000 claims description 10
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 claims description 6
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 claims description 5
- 239000000375 suspending agent Substances 0.000 claims description 5
- 239000004034 viscosity adjusting agent Substances 0.000 claims description 5
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- WMIYKQLTONQJES-UHFFFAOYSA-N hexafluoroethane Chemical compound FC(F)(F)C(F)(F)F WMIYKQLTONQJES-UHFFFAOYSA-N 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 3
- 230000008685 targeting Effects 0.000 claims description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- 239000013554 lipid monolayer Substances 0.000 claims description 2
- 150000003904 phospholipids Chemical class 0.000 claims description 2
- 239000000032 diagnostic agent Substances 0.000 claims 2
- 229940039227 diagnostic agent Drugs 0.000 claims 2
- 150000002632 lipids Chemical class 0.000 abstract description 28
- 239000000725 suspension Substances 0.000 abstract description 6
- 230000000087 stabilizing effect Effects 0.000 abstract description 4
- 238000002059 diagnostic imaging Methods 0.000 abstract 1
- 239000007792 gaseous phase Substances 0.000 abstract 1
- 238000002595 magnetic resonance imaging Methods 0.000 abstract 1
- 238000012285 ultrasound imaging Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 230000000694 effects Effects 0.000 description 26
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 22
- 238000000034 method Methods 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 16
- 210000001519 tissue Anatomy 0.000 description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 229920000642 polymer Polymers 0.000 description 14
- 230000008859 change Effects 0.000 description 13
- 229960005150 glycerol Drugs 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003745 diagnosis Methods 0.000 description 11
- 230000010355 oscillation Effects 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 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 10
- 238000011161 development Methods 0.000 description 10
- 230000018109 developmental process Effects 0.000 description 10
- 235000011187 glycerol Nutrition 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- 239000008187 granular material Substances 0.000 description 9
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical class O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- 238000009826 distribution Methods 0.000 description 8
- 229960004063 propylene glycol Drugs 0.000 description 8
- 235000013772 propylene glycol Nutrition 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 239000012177 spermaceti Substances 0.000 description 7
- 229940084106 spermaceti Drugs 0.000 description 7
- 239000003381 stabilizer Substances 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- 229910052724 xenon Inorganic materials 0.000 description 7
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 7
- 239000000654 additive Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000005291 magnetic effect Effects 0.000 description 6
- 239000011572 manganese Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 229910052754 neon Inorganic materials 0.000 description 6
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 150000005846 sugar alcohols Polymers 0.000 description 6
- 238000002604 ultrasonography Methods 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 5
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 239000000440 bentonite Substances 0.000 description 5
- 229910000278 bentonite Inorganic materials 0.000 description 5
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 5
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 150000002772 monosaccharides Chemical class 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- TXLHNFOLHRXMAU-UHFFFAOYSA-N 2-(4-benzylphenoxy)-n,n-diethylethanamine;hydron;chloride Chemical compound Cl.C1=CC(OCCN(CC)CC)=CC=C1CC1=CC=CC=C1 TXLHNFOLHRXMAU-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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 4
- 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 4
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 229940107161 cholesterol Drugs 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- 150000002016 disaccharides Chemical class 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000003349 gelling agent Substances 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 230000002102 hyperpolarization Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 229960001855 mannitol Drugs 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 210000004165 myocardium Anatomy 0.000 description 4
- CRSOQBOWXPBRES-UHFFFAOYSA-N neopentane Chemical class CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229910052701 rubidium Inorganic materials 0.000 description 4
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 229960002920 sorbitol Drugs 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 230000007704 transition Effects 0.000 description 4
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical class CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- 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 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 208000001435 Thromboembolism Diseases 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 3
- 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 3
- 238000009835 boiling Methods 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000001307 helium Substances 0.000 description 3
- 229910052734 helium Inorganic materials 0.000 description 3
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 235000013847 iso-butane Nutrition 0.000 description 3
- 229910052748 manganese Inorganic materials 0.000 description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 3
- QVGXLLKOCUKJST-OUBTZVSYSA-N oxygen-17 atom Chemical compound [17O] QVGXLLKOCUKJST-OUBTZVSYSA-N 0.000 description 3
- 229960004624 perflexane Drugs 0.000 description 3
- ZJIJAJXFLBMLCK-UHFFFAOYSA-N perfluorohexane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZJIJAJXFLBMLCK-UHFFFAOYSA-N 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 239000001294 propane Substances 0.000 description 3
- 208000002815 pulmonary hypertension Diseases 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 210000000582 semen Anatomy 0.000 description 3
- 238000004513 sizing Methods 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- 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 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 description 2
- CQTRUFMMCCOKTA-UHFFFAOYSA-N 4-amino-4-methylpentan-2-one Chemical compound CC(=O)CC(C)(C)N CQTRUFMMCCOKTA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- BHYOQNUELFTYRT-UHFFFAOYSA-N Cholesterol sulfate Natural products C1C=C2CC(OS(O)(=O)=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 BHYOQNUELFTYRT-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose 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)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 2
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229930186217 Glycolipid Natural products 0.000 description 2
- WQZGKKKJIJFFOK-VSOAQEOCSA-N L-altropyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-VSOAQEOCSA-N 0.000 description 2
- 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 2
- 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 2
- 241000124008 Mammalia Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 244000270834 Myristica fragrans Species 0.000 description 2
- 235000009421 Myristica fragrans Nutrition 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 108010039918 Polylysine Proteins 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000007824 aliphatic compounds Chemical class 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 235000012216 bentonite Nutrition 0.000 description 2
- 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 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- JJWKPURADFRFRB-UHFFFAOYSA-N carbonyl sulfide Chemical compound O=C=S JJWKPURADFRFRB-UHFFFAOYSA-N 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- BHYOQNUELFTYRT-DPAQBDIFSA-N cholesterol sulfate Chemical compound C1C=C2C[C@@H](OS(O)(=O)=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 BHYOQNUELFTYRT-DPAQBDIFSA-N 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000005686 electrostatic field Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 238000007046 ethoxylation reaction Methods 0.000 description 2
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000000004 hemodynamic effect Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 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 2
- 230000003993 interaction Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000001282 iso-butane Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 150000002634 lipophilic molecules Chemical class 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000003295 lusitropic effect Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDJAEZRIGNCQBZ-UHFFFAOYSA-N methylcyclobutane Chemical compound CC1CCC1 BDJAEZRIGNCQBZ-UHFFFAOYSA-N 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001702 nutmeg Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pent-2-ene Chemical group CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920000656 polylysine Polymers 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 235000010241 potassium sorbate Nutrition 0.000 description 2
- 239000004302 potassium sorbate Substances 0.000 description 2
- 229940069338 potassium sorbate Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 235000021251 pulses Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 2
- 229940082004 sodium laurate Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 230000003019 stabilising effect Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- WGUJEENXHVOHPK-UHFFFAOYSA-M (3-benzyl-2-methylundecan-2-yl)-tris-decylazanium bromide Chemical compound [Br-].C(C1=CC=CC=C1)C(C([N+](CCCCCCCCCC)(CCCCCCCCCC)CCCCCCCCCC)(C)C)CCCCCCCC WGUJEENXHVOHPK-UHFFFAOYSA-M 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- OWXJKYNZGFSVRC-NSCUHMNNSA-N (e)-1-chloroprop-1-ene Chemical compound C\C=C\Cl OWXJKYNZGFSVRC-NSCUHMNNSA-N 0.000 description 1
- OWXJKYNZGFSVRC-IHWYPQMZSA-N (z)-1-chloroprop-1-ene Chemical group C\C=C/Cl OWXJKYNZGFSVRC-IHWYPQMZSA-N 0.000 description 1
- KWXGJTSJUKTDQU-UHFFFAOYSA-N 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-8-iodooctane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I KWXGJTSJUKTDQU-UHFFFAOYSA-N 0.000 description 1
- MPEFSWGYIJNMCW-UHFFFAOYSA-N 1,1,1,2,2,3,4,4,4-nonafluoro-3-(trifluoromethyl)butane Chemical compound FC(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F MPEFSWGYIJNMCW-UHFFFAOYSA-N 0.000 description 1
- SUAMPXQALWYDBK-UHFFFAOYSA-N 1,1,1,2,2,3-hexafluoropropane Chemical compound FCC(F)(F)C(F)(F)F SUAMPXQALWYDBK-UHFFFAOYSA-N 0.000 description 1
- NYAZEAIBIYGMKL-UHFFFAOYSA-N 1,1,1,2,2-pentafluoro-2-nitroethane Chemical compound [O-][N+](=O)C(F)(F)C(F)(F)F NYAZEAIBIYGMKL-UHFFFAOYSA-N 0.000 description 1
- PWWKERINVYVSIE-UHFFFAOYSA-N 1,1,3,3-tetrafluoropropa-1,2-diene Chemical compound FC(F)=C=C(F)F PWWKERINVYVSIE-UHFFFAOYSA-N 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
- 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
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-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
- HEVGGTGPGPKZHF-UHFFFAOYSA-N 1-(1,2-dimethyl-3-methylidenecyclopentyl)-4-methylbenzene Chemical class CC1C(=C)CCC1(C)C1=CC=C(C)C=C1 HEVGGTGPGPKZHF-UHFFFAOYSA-N 0.000 description 1
- RUAUPNFNQOGIFF-UHFFFAOYSA-N 1-(4-tert-butyl-2,5-dimethoxyphenyl)propan-2-amine Chemical compound COC1=CC(C(C)(C)C)=C(OC)C=C1CC(C)N RUAUPNFNQOGIFF-UHFFFAOYSA-N 0.000 description 1
- RFCAUADVODFSLZ-UHFFFAOYSA-N 1-Chloro-1,1,2,2,2-pentafluoroethane Chemical compound FC(F)(F)C(F)(F)Cl RFCAUADVODFSLZ-UHFFFAOYSA-N 0.000 description 1
- PCPYTNCQOSFKGG-UHFFFAOYSA-N 1-chlorobuta-1,3-diene Chemical class ClC=CC=C PCPYTNCQOSFKGG-UHFFFAOYSA-N 0.000 description 1
- ZJSKEGAHBAHFON-UHFFFAOYSA-N 1-ethenyl-3-fluorobenzene Chemical compound FC1=CC=CC(C=C)=C1 ZJSKEGAHBAHFON-UHFFFAOYSA-N 0.000 description 1
- QURAFZQEKVYCBN-UHFFFAOYSA-N 1-fluoro-1-nitropropane Chemical compound CCC(F)[N+]([O-])=O QURAFZQEKVYCBN-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical class CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 1
- SFFUEHODRAXXIA-UHFFFAOYSA-N 2,2,2-trifluoroacetonitrile Chemical compound FC(F)(F)C#N SFFUEHODRAXXIA-UHFFFAOYSA-N 0.000 description 1
- OHMHBGPWCHTMQE-UHFFFAOYSA-N 2,2-dichloro-1,1,1-trifluoroethane Chemical compound FC(F)(F)C(Cl)Cl OHMHBGPWCHTMQE-UHFFFAOYSA-N 0.000 description 1
- VPTSQBHQXVQANU-UHFFFAOYSA-N 2,3,6-trimethylpiperidine Chemical class CC1CCC(C)C(C)N1 VPTSQBHQXVQANU-UHFFFAOYSA-N 0.000 description 1
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-N 2-(trimethylazaniumyl)ethyl hydrogen phosphate Chemical class C[N+](C)(C)CCOP(O)([O-])=O YHHSONZFOIEMCP-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- KIHBGTRZFAVZRV-UHFFFAOYSA-N 2-Hydroxyoctadecanoic acid Natural products CCCCCCCCCCCCCCCCC(O)C(O)=O KIHBGTRZFAVZRV-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- HAIGSNHRJAADFJ-UHFFFAOYSA-N 2-bromobutanal Chemical compound CCC(Br)C=O HAIGSNHRJAADFJ-UHFFFAOYSA-N 0.000 description 1
- XLMXUUQMSMKFMH-UZRURVBFSA-N 2-hydroxyethyl (z,12r)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCCO XLMXUUQMSMKFMH-UZRURVBFSA-N 0.000 description 1
- RMGHERXMTMUMMV-UHFFFAOYSA-N 2-methoxypropane Chemical class COC(C)C RMGHERXMTMUMMV-UHFFFAOYSA-N 0.000 description 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- BOFLDKIFLIFLJA-UHFFFAOYSA-N 2-methylbut-1-en-3-yne Chemical group CC(=C)C#C BOFLDKIFLIFLJA-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- USCSRAJGJYMJFZ-UHFFFAOYSA-N 3-methyl-1-butyne Chemical group CC(C)C#C USCSRAJGJYMJFZ-UHFFFAOYSA-N 0.000 description 1
- XPWHRQHBPRSUAW-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-[1-(1,2-oxazol-3-ylmethyl)piperidin-4-yl]imidazol-4-yl]pyrimidin-2-amine Chemical compound NC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)C2CCN(CC3=NOC=C3)CC2)=N1 XPWHRQHBPRSUAW-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- LPEKGGXMPWTOCB-UHFFFAOYSA-N 8beta-(2,3-epoxy-2-methylbutyryloxy)-14-acetoxytithifolin Chemical class COC(=O)C(C)O LPEKGGXMPWTOCB-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 241001502050 Acis Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- NDRMTEHNDRRELF-UHFFFAOYSA-N CCCCCCCCCCCCCCC(CC1=CC=CC=C1)C(C)(C)Cl.N Chemical compound CCCCCCCCCCCCCCC(CC1=CC=CC=C1)C(C)(C)Cl.N NDRMTEHNDRRELF-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- CXRFDZFCGOPDTD-UHFFFAOYSA-M Cetrimide Chemical compound [Br-].CCCCCCCCCCCCCC[N+](C)(C)C CXRFDZFCGOPDTD-UHFFFAOYSA-M 0.000 description 1
- XWCDCDSDNJVCLO-UHFFFAOYSA-N Chlorofluoromethane Chemical compound FCCl XWCDCDSDNJVCLO-UHFFFAOYSA-N 0.000 description 1
- 239000004340 Chloropentafluoroethane Substances 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- YTBSYETUWUMLBZ-UHFFFAOYSA-N D-Erythrose Natural products OCC(O)C(O)C=O YTBSYETUWUMLBZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-WHZQZERISA-N D-aldose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-WHZQZERISA-N 0.000 description 1
- YTBSYETUWUMLBZ-IUYQGCFVSA-N D-erythrose Chemical compound OC[C@@H](O)[C@@H](O)C=O YTBSYETUWUMLBZ-IUYQGCFVSA-N 0.000 description 1
- HAIWUXASLYEWLM-UHFFFAOYSA-N D-manno-Heptulose Natural products OCC1OC(O)(CO)C(O)C(O)C1O HAIWUXASLYEWLM-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- ZAQJHHRNXZUBTE-NQXXGFSBSA-N D-ribulose Chemical compound OC[C@@H](O)[C@@H](O)C(=O)CO ZAQJHHRNXZUBTE-NQXXGFSBSA-N 0.000 description 1
- ZAQJHHRNXZUBTE-UHFFFAOYSA-N D-threo-2-Pentulose Natural products OCC(O)C(O)C(=O)CO ZAQJHHRNXZUBTE-UHFFFAOYSA-N 0.000 description 1
- YTBSYETUWUMLBZ-QWWZWVQMSA-N D-threose Chemical compound OC[C@@H](O)[C@H](O)C=O YTBSYETUWUMLBZ-QWWZWVQMSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102100021238 Dynamin-2 Human genes 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010056474 Erythrosis Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- LSRGXLRLWFDKNR-UHFFFAOYSA-N FC(F)(F)[S] Chemical compound FC(F)(F)[S] LSRGXLRLWFDKNR-UHFFFAOYSA-N 0.000 description 1
- MBMLMWLHJBBADN-UHFFFAOYSA-N Ferrous sulfide Chemical compound [Fe]=S MBMLMWLHJBBADN-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 244000287680 Garcinia dulcis Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-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
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 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
- 101000817607 Homo sapiens Dynamin-2 Proteins 0.000 description 1
- 239000009636 Huang Qi Substances 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- HSNZZMHEPUFJNZ-UHFFFAOYSA-N L-galacto-2-Heptulose Natural products OCC(O)C(O)C(O)C(O)C(=O)CO HSNZZMHEPUFJNZ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 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
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 241000283222 Physeter catodon Species 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- BVCHSULSOLWKSB-UHFFFAOYSA-N S(=O)=Cl.C(F)(F)F Chemical compound S(=O)=Cl.C(F)(F)F BVCHSULSOLWKSB-UHFFFAOYSA-N 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- HAIWUXASLYEWLM-AZEWMMITSA-N Sedoheptulose Natural products OC[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@](O)(CO)O1 HAIWUXASLYEWLM-AZEWMMITSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004283 Sodium sorbate Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 240000001058 Sterculia urens Species 0.000 description 1
- 235000015125 Sterculia urens Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical class C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical class 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
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- NOSIYYJFMPDDSA-UHFFFAOYSA-N acepromazine Chemical compound C1=C(C(C)=O)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 NOSIYYJFMPDDSA-UHFFFAOYSA-N 0.000 description 1
- 229960005054 acepromazine Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001361 allenes Chemical class 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- JBIROUFYLSSYDX-UHFFFAOYSA-M benzododecinium chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 JBIROUFYLSSYDX-UHFFFAOYSA-M 0.000 description 1
- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 description 1
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 description 1
- DLNWMWYCSOQYSQ-UHFFFAOYSA-M benzyl-hexadecyl-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 DLNWMWYCSOQYSQ-UHFFFAOYSA-M 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 210000000746 body region Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- YNKZSBSRKWVMEZ-UHFFFAOYSA-N bromo-chloro-fluoromethane Chemical compound FC(Cl)Br YNKZSBSRKWVMEZ-UHFFFAOYSA-N 0.000 description 1
- LHMHCLYDBQOYTO-UHFFFAOYSA-N bromofluoromethane Chemical compound FCBr LHMHCLYDBQOYTO-UHFFFAOYSA-N 0.000 description 1
- LLCSWKVOHICRDD-UHFFFAOYSA-N buta-1,3-diyne Chemical group C#CC#C LLCSWKVOHICRDD-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- WFYPICNXBKQZGB-UHFFFAOYSA-N butenyne Chemical group C=CC#C WFYPICNXBKQZGB-UHFFFAOYSA-N 0.000 description 1
- QQHZPQUHCAKSOL-UHFFFAOYSA-N butyl nitrate Chemical compound CCCCO[N+]([O-])=O QQHZPQUHCAKSOL-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000000828 canola oil Substances 0.000 description 1
- 235000019519 canola oil Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZRZHWNKHBGRJKD-UHFFFAOYSA-N chloro(dinitro)methane Chemical compound [O-][N+](=O)C(Cl)[N+]([O-])=O ZRZHWNKHBGRJKD-UHFFFAOYSA-N 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 235000019406 chloropentafluoroethane Nutrition 0.000 description 1
- 230000003098 cholesteric effect Effects 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- UMNKXPULIDJLSU-UHFFFAOYSA-N dichlorofluoromethane Chemical compound FC(Cl)Cl UMNKXPULIDJLSU-UHFFFAOYSA-N 0.000 description 1
- 229940099364 dichlorofluoromethane Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- UYAAVKFHBMJOJZ-UHFFFAOYSA-N diimidazo[1,3-b:1',3'-e]pyrazine-5,10-dione Chemical compound O=C1C2=CN=CN2C(=O)C2=CN=CN12 UYAAVKFHBMJOJZ-UHFFFAOYSA-N 0.000 description 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- XJWSAJYUBXQQDR-UHFFFAOYSA-M dodecyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)C XJWSAJYUBXQQDR-UHFFFAOYSA-M 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical class C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- FOTXAJDDGPYIFU-UHFFFAOYSA-N ethylcyclopropane Chemical compound CCC1CC1 FOTXAJDDGPYIFU-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 150000002190 fatty acyls Chemical group 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- RAKXKOSFSGNFHY-UHFFFAOYSA-N fluoro(nitro)methane Chemical compound [O-][N+](=O)CF RAKXKOSFSGNFHY-UHFFFAOYSA-N 0.000 description 1
- XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical group FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 1
- LRKXKCCGHUZTEB-UHFFFAOYSA-N fluoroform;sulfuryl difluoride Chemical compound FC(F)F.FS(F)(=O)=O LRKXKCCGHUZTEB-UHFFFAOYSA-N 0.000 description 1
- XGVXNTVBGYLJIR-UHFFFAOYSA-N fluoroiodomethane Chemical compound FCI XGVXNTVBGYLJIR-UHFFFAOYSA-N 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- BJHIKXHVCXFQLS-UYFOZJQFSA-N fructose group Chemical group OCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- QPJBWNIQKHGLAU-IQZHVAEDSA-N ganglioside GM1 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](NC(=O)CCCCCCCCCCCCCCCCC)[C@H](O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 QPJBWNIQKHGLAU-IQZHVAEDSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 231100000734 genotoxic potential Toxicity 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 210000002989 hepatic vein Anatomy 0.000 description 1
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 235000014304 histidine Nutrition 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 208000006278 hypochromic anemia Diseases 0.000 description 1
- 125000002951 idosyl group Chemical class C1([C@@H](O)[C@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 229940075495 isopropyl palmitate Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000010358 mechanical oscillation Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 229940057867 methyl lactate Drugs 0.000 description 1
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical class CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical class COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- VNXBKJFUJUWOCW-UHFFFAOYSA-N methylcyclopropane Chemical compound CC1CC1 VNXBKJFUJUWOCW-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- CQWWONKCVFKXRE-UHFFFAOYSA-N n,n-dimethylethanamine;hydrobromide Chemical compound [Br-].CC[NH+](C)C CQWWONKCVFKXRE-UHFFFAOYSA-N 0.000 description 1
- KSKTVNNRMXUMIY-UHFFFAOYSA-N n,n-dimethylethanamine;hydrochloride Chemical compound Cl.CCN(C)C KSKTVNNRMXUMIY-UHFFFAOYSA-N 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- QEUWOEGDLXKUNJ-UHFFFAOYSA-N naphthalene;hydrofluoride Chemical class F.C1=CC=CC2=CC=CC=C21 QEUWOEGDLXKUNJ-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- RKSFWNXSXBDVII-UHFFFAOYSA-N nonadecane-1,2,3-tricarboxylic acid Chemical class CCCCCCCCCCCCCCCCC(C(O)=O)C(C(O)=O)CC(O)=O RKSFWNXSXBDVII-UHFFFAOYSA-N 0.000 description 1
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- BCCOBQSFUDVTJQ-UHFFFAOYSA-N octafluorocyclobutane Chemical compound FC1(F)C(F)(F)C(F)(F)C1(F)F BCCOBQSFUDVTJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019407 octafluorocyclobutane Nutrition 0.000 description 1
- 229940060184 oil ingredients Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical class CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 1
- 230000005408 paramagnetism Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 229940059574 pentaerithrityl Drugs 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical group CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 229950001552 perflisopent Drugs 0.000 description 1
- 229950011087 perflunafene Drugs 0.000 description 1
- UWEYRJFJVCLAGH-IJWZVTFUSA-N perfluorodecalin Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)[C@@]2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[C@@]21F UWEYRJFJVCLAGH-IJWZVTFUSA-N 0.000 description 1
- LGUZHRODIJCVOC-UHFFFAOYSA-N perfluoroheptane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F LGUZHRODIJCVOC-UHFFFAOYSA-N 0.000 description 1
- JAJLKEVKNDUJBG-UHFFFAOYSA-N perfluorotripropylamine Chemical compound FC(F)(F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F JAJLKEVKNDUJBG-UHFFFAOYSA-N 0.000 description 1
- CNVZJPUDSLNTQU-SEYXRHQNSA-N petroselinic acid Chemical class CCCCCCCCCCC\C=C/CCCCC(O)=O CNVZJPUDSLNTQU-SEYXRHQNSA-N 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
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000008106 phosphatidylserines Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229950000845 politef Drugs 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920006389 polyphenyl polymer Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
- NRTBZBYBLPEOCE-UHFFFAOYSA-L potassium;sodium;sulfite Chemical compound [Na+].[K+].[O-]S([O-])=O NRTBZBYBLPEOCE-UHFFFAOYSA-L 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 229940116423 propylene glycol diacetate Drugs 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- HSNZZMHEPUFJNZ-SHUUEZRQSA-N sedoheptulose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO HSNZZMHEPUFJNZ-SHUUEZRQSA-N 0.000 description 1
- 239000005368 silicate glass Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 235000021309 simple sugar Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002328 sterol group Chemical group 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003505 terpenes Chemical group 0.000 description 1
- SNIFAVVHRQZYGO-UHFFFAOYSA-N tetradec-5-ene Chemical class CCCCCCCCC=CCCCC SNIFAVVHRQZYGO-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- BPXRXDJNYFWRDI-UHFFFAOYSA-N trifluoro(trifluoromethylperoxy)methane Chemical compound FC(F)(F)OOC(F)(F)F BPXRXDJNYFWRDI-UHFFFAOYSA-N 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- AISMNBXOJRHCIA-UHFFFAOYSA-N trimethylazanium;bromide Chemical compound Br.CN(C)C AISMNBXOJRHCIA-UHFFFAOYSA-N 0.000 description 1
- NXHILIPIEUBEPD-UHFFFAOYSA-H tungsten hexafluoride Chemical compound F[W](F)(F)(F)(F)F NXHILIPIEUBEPD-UHFFFAOYSA-H 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 229940032912 zephiran Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
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
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6925—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1806—Suspensions, emulsions, colloids, dispersions
- A61K49/1815—Suspensions, emulsions, colloids, dispersions compo-inhalant, e.g. breath tests
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/046—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/14—Liposomes; Vesicles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
- A61K8/70—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine containing perfluoro groups, e.g. perfluoroethers
-
- 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
-
- 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
-
- 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
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
- G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
- G01R33/48—NMR imaging systems
- G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
- G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
- G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/87—Application Devices; Containers; Packaging
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/3145—Filters incorporated in syringes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2984—Microcapsule with fluid core [includes liposome]
Abstract
本发明公开了装有类脂水悬浮液相和与含水稳定化相基本上分离的气相的容器,该容器可用于诊断显影如超声和核磁共振显影以及可用于治疗应用。
Description
本申请是1993年11月30日申请的序号为No.159,687的美国申请的部分后续申请,而No.159,687又是1993年6月11日申请的序号为No.076,239的美国申请的部分后续申请,而No.076,239又是1991年6月18日申请的序号为No.717,084和No.716,899的美国申请的部分后续申请,而No.717,084和No.716,899又都是1990年8月20日申请的序号为No.569,828的美国申请的部分后续申请,而No.569,828又是1989年12月22日申请的序号为No.455,707的美国申请的部分后续申请。
本申请也是1993年11月30日申请的序号为No.160,232的美国申请的部分后续申请,而No.160,232又是1993年6月11日申请的序号为No.076,250的美国申请的部分后续申请,而No.076,250又是1991年6月18日申请的序号为No.717,084和No.716,899的两个美国申请的部分后续申请,而No.717,084和No.716,899又都是1990年8月20目申请的序号为No.569,828的美国申请的部分后续申请,而No.569,828又是1989年12月22日申请的序号为No.455,707的美国申请的部分后续申请。
本申请还是1994年3月11日申请的序号为No.212,533的美国申请的部分后续申请,而No.212,533又是1993年6月11日申请的序号为No.076,239和No.076,250的两个美国申请的部分后续申请。No.076,239和No.076,250的两个美国申请的来龙去脉如上文所列。
本申请在此要求这些申请的优先权,并且这些申请均以其全文所公开的内容引入本文作参考。
本发明的背景
超声是一种比其它诊断方法有许多优越性的诊断显影技术。与核医学和X射线等显影技术不同,超声不使患者遭受电离辐射的有害影响。而且,相对来讲超声不贵并且可进行便携式检查。
在超声显影中,声音是通过转换器被传递到患者或动物体内的。当声波通过体内传播时,它们会碰到组织和流体的界面。取决于体内的组织和流体的声学性质,超声波部分地或全部地被反射或吸收。当声波被界面反射时,它们被转换器内的接收器探测并被加工以形成影像。体内的组织和流体的声学性质,决定了所得影像的对比度。
核磁共振显影(MRI)是相对新颖的显影技术,与X射线不同,它不利用电离辐射。同计算机化X射线断层照相术一样,MRI能产生身体的横断面影像,然而,MRI还有可在任何扫描平面(即,轴向的、头顶的、前后向的或正交的)产生影像的优点。
MRI利用磁场、高频能量和磁场梯度来产生身体的影像。组织间的对比或信号强度的差异大体反映了组织的T1和T2松驰值和质子密度(有效地反映了自由水的含量)。
近几年在诊断超声和MRI技术方面已经取得了进展。然后,尽管已在各方面进行了技术改进,超声和MRI在许多方面还仍不完美,尤其是在肝脏、脾脏、肾脏、心脏和脉管系统的显影和疾病的探查(包括血流的测量)方面。对这些区域的探测能力以及进行所述测量的能力,依赖于组织或流体与其周围组织或流体间的声学性质(超声)或T1和T2的信号强度(MRI)差异。因此,人们一直在寻求使组织或流体与其周围组织或流体间差异增加以及改善超声或核磁共振显影和疾病检查的造影剂。
本发明通过提供装有类脂水悬浮液相和与该类脂水悬浮液相基本分离的气相的便利容器来解决这些以及其它的问题,在使用前振荡所述的便利容器,产生用于诸如超声或核磁共振显影以及其它用途的极佳的气体填充的脂质体造影剂。因造影剂是在使用之前刚刚制备的,则可避免其储藏有效期稳定性的问题。
本发明概述
本发明提供一种容器,容器内装有(i)类脂水悬浮液相和(ii)与该类脂水悬浮液相基本分离的气相。在使用前,可以振荡容器的内容物,由此产生气体填充的脂质体组合物,该组合物是用于例如超声或核磁共振显影以及治疗应用的具极佳均一性的造影剂。
根据本发明刚好在使用前才制备造影剂的能力避免了现有技术中的许多造影剂遇到的储藏有效期稳定性的问题。本发明的自给装置使灭菌也很容易。
下面对本发明的这些和其它的方面及优点进行更详细地讨论。
附图的简要说明
图1是装有类脂水悬浮液和与之基本分离的液面上气体的容器的侧切视图。
图2是振荡装置图,它可用于振荡图1的容器,由此混合类脂水悬浮液和气体,并产生用于超声或核磁共振显影的造影剂。
图3是用图1所示的容器和图2所示的振荡装置产生的气体填充的脂质体的显微照片。
本发明的详细描述
本发明的容器装有类脂水悬浮液相和基本分离的气相。在使用前,可振荡容器及其内容物,使类脂和气相混合,导致气体填充脂质体的形成,该脂质体包裹了气体。所得的气体填充的脂质体提供了用于诊断显影、尤其是用于超声或核磁共振显影的极佳的强造影剂。
许多类脂可用于所述的类脂水悬浮液相。根据需要,类脂可以悬饱和的或不饱和的,可以是直链的或支链形的。这样的类脂可以包括,例如,含有宽范围碳原子数、优选在大约12个碳原子和大约22个碳原子之间的脂肪酸分子。也可使用由类异戊二烯单元、异戊烯基、和/或甾醇部分(例如胆甾醇、胆甾醇硫酸酯、及其类似物)组成的烃类。如果需要,类脂也可以带有聚合物链如两亲聚合物聚乙二醇(PEG)或聚乙烯吡咯烷酮(PVP)或其衍生物(用于体内靶向),或带电荷氨基酸如聚赖氨酸或聚精氨酸(用于结合带负电荷的化合物)或糖类(用于体内靶向)例如记载于No.4,310,505的美国专利中的糖类、或糖脂(用于体内靶向)、或抗体及其它的肽及蛋白质(用于体内靶向)等等。可将靶向或结合化合物简单地加入到类脂水悬浮液相中,或者将其特异性地化学连接到类脂上。如果需要,类脂也可以是阴离子类脂或阳离子类脂,以便它们自己也能与其它化合物如药物、遗传物质、或其它治疗剂结合。
适当的类脂和特别适当的类脂类别的例子包括:磷脂酰胆碱类,如二油酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱(DPPC)、和二硬脂酰磷脂酰胆碱;磷脂酰乙醇胺类,如二棕榈酰磷脂酰乙醇胺(DPPE)、二油酰磷脂酰乙醇胺和N-琥珀酰-二油酰磷脂酰乙醇胺;磷脂酰丝氨酸类;磷脂酰甘油类;鞘脂类;糖脂类(glycolipids)如神经节苷脂GM1;糖脂类(glucolipids);硫苷脂类;糖鞘脂类;磷脂酸类如二棕榈酰磷脂酸(DPPA);棕榈酸类;硬脂酸类;花生四烯酸类;月桂酸类;肉豆蔻酸类;月桂烯酸类;抹香鲸酸类;9-十四碳烯酸类;9-十六碳烯酸类;6-十八碳烯酸类;油脂酸类;异月桂酸类;异肉豆蔻酸类;异棕榈酸类;异硬脂酸类;胆甾醇和胆甾醇的衍生物如胆甾醇半琥珀酸酯、胆甾醇硫酸酯、和胆甾醇-(4′-三甲氨基)-丁酸酯;聚氧乙烯脂肪酸酯类;聚氧乙烯脂肪酸醇类;聚氧乙烯脂肪酸醇醚;聚氧乙烯化的山梨糖醇酐脂肪酸酯;甘油聚乙烯乙二醇羟基硬脂酸酯;甘油聚乙烯乙二醇蓖麻醇酸酯;乙氧基化的大豆甾醇类;乙氧基化的蓖麻油;聚氧乙烯-聚氧丙烯脂肪聚合物类;聚氧乙烯脂肪酸硬脂酸酯类;12-(((7′-二乙氨基香豆素-3-基)-羰基)-甲氨基)-十八烷酸;N-[12-(((7′-二乙氨基-香豆素-3-基)-羰基-甲基-氨基)十八烷酰基]-2-氨基-棕榈酸;1,2-二棕榈酰基-Sn-甘油;1,2-二棕榈酰基-Sn-3-琥珀酰甘油;1,3-二棕榈酰基-2-琥珀酰基-甘油;和1-十六烷基-2-棕榈酰基-甘油磷酰乙醇胺和棕榈酰基高半胱氨酸;月桂基三甲基溴化铵(月桂基=十二烷基);鲸腊基三甲基溴化铵(鲸腊基=十六烷基);肉豆蔻基三甲基溴化铵(肉豆蔻基=十四烷基);烷基二甲基苄基氯化铵,如其中的烷基为C12、C14或C16烷基;苄基二甲基十二烷基溴化铵;苄基二甲基十二烷基氯化铵;苄基二甲基十六烷基溴化铵;苄基二甲基十六烷基氯化铵;苄基二甲基十四烷基溴化铵;苄基二甲基十四烷基氯化铵;鲸腊基二甲基乙基溴化铵;鲸腊基二甲基乙基氯化铵;溴化鲸腊基吡啶翁;氯化鲸腊基吡啶翁;N-[1-(2,3-二油酰氧基)-丙基]-N,N,N-三甲基氯化铵(DOTMA);1,2-二油酰氧基-3-(三甲氨基)丙烷(DOTAP);和1,2-二油酰基-e-(4′-三甲氨基)-丁酰基-Sn-甘油(DOTB)。
一旦本领域的技术人员掌握了本发明公开的内容,对于他们来讲,显然上面所列的类脂仅是示例性的并且也可使用其它的类脂、脂肪酸、和衍生物以及它们的混合物,而且这些额外的化合物也将落入本文所用的术语类脂的范围之内。正如熟练的技术人员会认识到的,所述的类脂和/或其混合物,可通过振荡容器形成脂质体(也就是具有内部空腔的脂质球),所述脂质体在其内部空腔包裹了来自气相的气体。该脂质体可由单层类脂层(类脂单层)组成,也可由两层类脂层(类脂双层)或两层以上的类脂层(类脂多层)组成。
一般说来,类脂优选以其凝胶状态存在,也就是说,在低于类脂物质的凝胶态向液晶态转变的相变温度(Tm)下存在,尤其是在振荡期间。各种不同类脂的凝胶态向液晶态转变的相变温度是已知的。用已熟知的技术也可容易地将这些温度计算出来。下表1摘自Derek Marsh的“CRC Handbook of Lipid Bilayers”(CRC类脂双层手册),139页,CRC出版,Boca Raton,佛罗里达州(1990)。表1显示了例如,各种有代表性的饱和胆碱磷酸类脂的主链相变温度。
表1
饱和的二脂酰基-Sn-甘油基-(3)-胆碱磷酸类:主链熔解转变
脂酰基键中的碳 | 主相变温度℃ |
1,2-(12∶0)1,2-(13∶0)1,2-(14∶0)1,2-(15∶0)1,2-(16∶0)1,2-(17∶0)1,2-(18∶0)1,2-(19∶0)1,2-(20∶0)1,2-(21∶0)1,2-(22∶0)1,2-(23∶0)1,2-(24∶0) | -1.013.723.534.541.448.255.161.864.571.174.079.580.1 |
在本发明的优选实施方案中,含水类脂相还包含聚合物,优选两亲聚合物,并优选与类脂直接结合(即,化学连接)的聚合物。两亲化合物优选为聚乙二醇或其衍生物。最优选的组合是与聚乙二醇(PEG)、特别是平均分子量为约5000的PEG结合的类脂二棕榈酰磷脂酰乙醇胺(DPPE)(DPPE-PEG5000)。PEG或其它聚合物可以通过共价键如酰胺键、氨基甲酸酯键或胺键与DPPE或其它类脂结合。另外,酯键、醚键、硫酯键、硫代酰胺键或二硫键(硫酯键)可用于PEG或其它聚合物而使聚合物与,例如,胆甾醇或其它磷脂类结合起来。特别优选的类脂组合是DPPC、DPPE-PEG5000和DPPA,尤其是以DPPC∶DPPE-PEG5000∶DPPA=约82%∶8%∶10%(摩尔百分比)的组合。
为制备含水相,可以将类脂与水(优选蒸馏水)、正常(生理)盐水、磷酸盐缓冲液或其它水溶液混合,这一点对于本领域的技术人员是显然的。
许多不同的气体可以用于本发明的气相。优选的气体是基本上不溶于类脂水悬浮液相的。“基本上不溶于”,是指气体在20℃和1个大气压下其在水中的溶解度维持在等于或小于18毫升气体/千克水。如此说来,基本上不溶的气体具有的溶解度小于氮气的溶解度。溶解度在20℃和1个大气压下优选等于或小于15毫升气体/千克水,更优选等于或小于10毫升气体/千克水。在前面所述的温度和压力下,一类优选的气体的溶解度为约0.001-约18毫升气体/千克水,或为约0.01-约15毫升气体/千克水,或为约0.1-约10毫升气体/千克水,或为约1-约8毫升气体/千克水,或为约2-约6毫升气体/千克水。例如,在20℃和1个大气压下,全氟代烃和氟化气体六氟化硫的溶解度小于10毫升气体/千克水,因此它们是优选的。不是基本上不溶的气体,如本文所定义的,是指可溶解的气体。
其它合适的基本上不溶或可溶的气体包括(但不限于):六氟丙酮、异丙基乙炔、丙二烯、四氟丙二烯、三氟化硼、1,2-丁二烯、1,2-丁二烯、1,2,3-三氯丁二烯、2-氟-1,3-丁二烯、2-甲基-1,3-丁二烯、六氟-1,3-丁二烯、丁二炔、1-氟丁烷、2-甲基丁烷、十氟丁烷(全氟丁烷)、十氟异丁烷(全氟异丁烷)、1-丁烯、2-丁烯、2-甲基-1-丁烯、3-甲基-1-丁烯、全氟-1-丁烯、全氟-2-丁烯、4-苯基-3-丁烯-2-酮、2-甲基-1-丁烯-3-炔、硝酸丁酯、1-丁炔、2-丁炔、2-氯-1,1,1,4,4,4-六氟-丁炔、3-甲基-1-丁炔、全氟-2-丁炔、2-溴-丁醛、硫化羰、丁烯腈、环丁烷、甲基环丁烷、八氟环丁烷(全氟环丁烷)、全氟异丁烷、3-氯环戊烯、环丙烷、1,2-二甲基环丙烷、1,1-二甲基环丙烷、乙基环丙烷、甲基环丙烷、联二炔、3-乙基-3-甲基二氮丙啶、1,1,1-三氟重氮乙烷、二甲胺、六氟二甲胺、二甲基乙基胺、双-(二甲基膦)胺、2,3-二甲基-2-降冰片烷、全氟二甲胺、氯化二甲基氧翁、1,3-二氧戊环-2-酮、1,1,1,2-四氟乙烷、1,1,1-三氟乙烷、1,1,12,2-四氟乙烷、1,1,1-三氟乙烷、1,1,2,2-四氟乙烷、1,1,2-三氯-1,2,2-三氟乙烷、1,1-二氯乙烷、1,1-二氯-1,2,2,2-四氟乙烷、1,2-二氟乙烷、1-氯-1,1,2,2,2-五氟乙烷、2-氯-1,1-二氟乙烷、1-氯-1,1,2,2,2-五氟乙烷、2-氯-1,1-二氟乙烷、1-氯-1,1,2,2-四氟乙烷、2-氯-1,1-二氟乙烷、氯乙烷、氯五氟乙烷、二氯三氟乙烷、氟乙烷、硝基五氟乙烷、亚硝基五氟-乙烷、全氟乙烷、全氟乙胺、乙基乙烯基醚、1,1-二氯乙烯、1,1-二氯-1,2-二氟-乙烯、1,2-二氟乙烯、甲烷、三氟甲烷磺酰氯、三氟甲烷磺酰氟、(五氟硫代)三氟甲烷、溴代-二氟代-亚硝基-甲烷、溴代-氟代-甲烷、溴代-氯代-氟代-甲烷、溴代-三氟代-甲烷、氯代-二氟代-硝基-甲烷、氯代-二硝基-甲烷、氯代-氟代-甲烷、氯代-三氟代-甲烷、氯代-二氟代-甲烷、二溴代-二氟代-甲烷、二氯代-二氟代-甲烷、二氯代-氟代-甲烷、二氟代-甲烷、二氟代-碘代-甲烷、二硅甲烷、氟代-甲烷、碘甲烷-碘代-三氟代-甲烷、硝基-三氟代-甲烷、亚硝基-三氟代-甲烷、四氟代-甲烷、三氯代-氟代-甲烷、三氟代-甲烷、三氟甲烷亚磺酰氯、2-甲基丁烷、甲醚、甲基异丙基醚、乳酸甲酯、亚硝酸甲酯、二甲硫、甲基乙烯基醚、新戊烷、氮气(N2)、氧化氮、1,2,3-十九烷三羧酸-2-羟基三甲基酯、1-壬烯-3-炔、氧气(O2)、氧17(17O2)、1,4-戊二烯、正-戊烷、十二氟戊烷(全氟戊烷)、十四氟己烷(全氟己烷)、全氟异戊烷、全氟新戊烷、4-氨基-4-甲基-2-戊酮、1-戊烯、2-戊烯(顺式)、2-戊烯(反式)、3-溴-1-戊烯、全氟代-1-戊烯、四氯代-苯二甲酸、2,3,6-三甲基-哌啶、丙烷、1,1,1,2,2,3-六氟-丙烷、1,2-环氧-丙烷、2,2-二氟丙烷、2-氨基-丙烷、2-氯-丙烷、七氟代-1-硝基-丙烷、七氟代-1-亚硝基-丙烷、全氟丙烷、丙烯、1,1,1,2,3,3-六氟-2,3-二氯-丙烷、1-氯-丙烯、氯丙烯(反式)、2-氯-丙烯、3-氟-丙烯、全氟代-丙烯、丙炔、3,3,3-三氟丙炔、3-氟-苯乙烯、六氟化硫、十氟化二硫(S2F10)、2,4-二氨基-甲苯、三氟乙腈、三氟甲基过氧化物、二(三氟甲基)硫、六氟化钨、乙烯基乙炔、乙烯基醚、氖气、氦气、氪气、氙气(特别是富含铷的超极化的氙气)、二氧化碳、氦气、和空气。优选氟化的气体(即,含有一个或多个氟分子的气体如六氟化硫)、碳氟化物气体(即,是氟化的碳或气体的氟化气体)、全氟化碳气体(即,被完全氟化的碳氟化物气体如全氟丙烷和全氟丁烷)。
虽然从理论上来讲,任何气体都可用于本发明的气相,但可对特定的气体加以选择,以使所得造影剂的所需特征最佳,并满足特定诊断应用的要求。已经发现,例如,某些气体在振摇后形成比其它气体更稳定的气体填充的脂质体,从而这些气体是优选的。还发现,某些气体在诊断显影如超声或MRI时产生较好的显影结果。
作为提高气体填充的脂质体稳定性的例子,人们发现二氧化碳<氧气<空气<氮气<氖气=氦气<全氟化碳气体。由于这些以及其它方面的原因,氟化的气体、尤其是全氟化碳气体是优选的。
另外,虽然在一些情况下,可溶性气体可起到与本发明的气相同样适当的作用,但是基本上不溶的气体倾向于比具有较高溶解度的气体产生更大的稳定性,特别是在通过振荡产生造影剂的时候。而且,根据本发明,在振荡前很容易使这些不溶性气体形成的气相基本上与含水类脂相保持分离。因此,如上文所定义的基本上不溶的气体是优选的。
超声显影的质量和超声显影的持续时间也与气体在含水环境中的溶解度有关。一般说来,气体的溶解度降低,可使超声得到持续时间较长、分辨率较高的图像。
另外,已普遍观察到振荡产生的气体填充的脂质体的大小与气体在含水环境中的溶解度有关,气体的溶解度较大导致产生较大的气体填充的脂质体。人们也相信脂质体的大小会受到气体与脂质体的内壁间的相互作用的影响。具体地讲,人们相信介面上的相互作用影响张力,结果使内部气体作用在脂质体的类脂内壁上的外向力受到影响。张力的减弱使脂质体变得较小,它是通过减小内部气体产生的力,从而使含水环境在脂质体的外面的力引起气体填充的脂质体收缩。
由于Henry′s公式通常适用于在直至大约1个大气压下对微溶的气体的计算,可用该公式估算气体在含水溶剂中的溶解度(Daniels,F.和Alberty,R.A.,Physical Chemistry(物理化学),第三版,Wiley& Sons公司,纽约,1966)。例如,空气在25℃时的溶解度为18.68ml/kg水,氮气在25℃的溶解度为约18.8mlkg-1。另一方面,六氟化硫在25℃的溶解度为约5.4mlkg-1。
总之,由于稳定性、不溶解性、和所得脂质体的大小方面的原因,优选氟化的气体、氟化碳气体、以及全氟化碳气体。尤其优选的是氟化的气体六氟化硫、以及全氟化碳气体全氟丙烷、全氟丁烷、全氟环丁烷、全氟甲烷、全氟乙烷、和全氟戊烷,特别优选的是全氟丙烷和全氟丁烷。
应注意到具有少于5个碳原子的全氟化碳在室温下是气体。例如,全氟戊烷在直到约27℃时还是液体。在该温度以上,它将占据容器的液面上空间。然而,已证明即使在室温下也可用全氟戊烷来填充空间液面上(也就是管形瓶内类脂悬浮液相上面的空间)。通过选择计算出的填充液面上空间的液体全氟戊烷的限定值并在低温下(例如在-20℃)将液体加入到容器中,然后对容器抽真空(有效地除去液面上空间的空气)并使容器密封,全氟戊烷将在低于其在1个大气压下的沸点的温度下进行液相到气相的转变。因此,在室温下它将以气体占据液面上的部分或全部空间。正如本领域的技术人员所能认识到的,人们可以通过运用通常的“拇指规则”估测法来估计出液相向气相转变温度的降低。具体地讲,压力每降低一半,沸点将下降约10℃。另外,人们可用建立在基于Boyle(玻义耳)定律的理想气体定律上的关系,计算出作为降低的压力函数的温度的降低。另一个用全氟戊烷填充液面上空间的方法是,先对液面上空间抽真空,然后在27℃以上用全氟戊烷填充液面上空间。当然,该方法不仅限用于全氟戊烷、它适用于所有的全氟化碳气体以及一般的气体,条件是气体的沸点是已知的。
如果需要,两种或更多的不同气体可以一起用来填充液面上空间。气体的混合物在所得的气体填充的脂质体的多种应用方面(如超声显影、MR显影等应用)有许多优点。还发现将少量的基本不溶的气体与可溶的气体混合提供了比该混合所预期的稳定性更大的稳定性。例如,可以将少量的(例如,通常至少为约1摩尔%)全氟化碳气体与空气、氮气、氧气、二氧化碳或其它更易溶的气体混合。振荡后产生的气体填充的脂质体造影剂比空气、氮气、氧气、二氧化碳或其它溶解性更强的气体本身更稳定。
另外,气体混合物的使用可用于弥补气体填充的脂质体大小的增大,否则要被注射到体内的含有纯全氟化碳气体的脂质体将会在体内发生增大。已经发现,一些全氟化碳气体可以吸收或吸入其它气体如氧气。因此,如果静脉注射全氟化碳气体时,它可以吸收溶解于循环血液中的氧气或其它可溶性气体。然后,作为该吸收的结果,所得的气泡可在体内长大。掌握了这些现象的知识,人们可以将全氟化碳气体与可溶性气体如空气、氮气、氧气、二氧化碳预混合,因而使全氟化碳的吸收或吸入性质饱和。结果,这将防止甚至根除气体填充的脂质体在血流中膨胀的可能性。如果脂质体能膨胀到大于10μm的大小,将其施用于血液中则可能发生危险的栓塞事件,基于这一事实,防止或根除气体填充的脂质体在血流中膨胀的可能性是重要的。通过用比全氟化碳气体更易溶的气体与全氟化碳气体一起填充液面上空间,在注射到体内后,气体填充的脂气体将一般不发生所述增大。因此,作为本发明的结果,脂质体膨胀产生栓塞事件的问题可通过产生根除了或有效地阻止了所述膨胀的脂质体而得以克服。
因此,根据本发明,如果需要,可将基本上不溶的气体与可溶的气体混合来有效地产生高效而稳定的气体填充的脂质体。
下表2列出了以不同比例的基本不溶的气体全氟丙烷(PFP)和空气作为液面上空间气体所制备的气体填充的脂质体样品的分析结果。以3300RPM振荡60秒,将气体与含水类脂相混合。用光学颗粒大小测定仪(Optical Partical Sizer(Particle Sizing System,SantaBarbara,CA))分析气体填充的脂质体大小和总数。每次分析用5微升的样品,每次测定用4个样品。
如表2所示,即使仅20%的气体是PFP(基本上不溶的气体)而80%的气体是空气(可溶性气体的混合物)时,也产生了比仅用空气(0%的PFP)时多100倍的脂质体。而且,当仅使用空气时(0%的PFP),脂质体更不稳定并且大多数的脂质体的大小在10微米以上。20%PFP和80%空气的脂质体,看来与80%PFP和20%空气的脂质体以及其它含中间浓度的PFP的样品同样地稳定,而且20%PFP和80%空气所产生的气体填充的脂质体与80%PFP和20%空气所产生的脂质体大约同样多。
表2
全氟丙烷的比例对气泡大小和数目的影响
气体%PFP | 数量加权均数 | 体积加权均数 | 估算的颗粒数 | 小于10μm的颗粒的百分数 | 估算的每毫升中的颗粒数 | 大于10μm的颗粒的百分数 |
80%平均数eSTDevCV | 2.370.073% | 28.760.823% | 5.45E+054.67E+049% | 98.940.080% | 1.10E+098 20E+077% | 1.050.077% |
60%平均数STDevCV | 2.140.021% | 20.755.9329% | 5.87E+057.08E+0412% | 99.360.100% | 1.15E+091.27E+0811% | 0.640.0914% |
50%平均数STDevCV | 2.130.073% | 30.3512.1540% | 5.23E+051.49E+043% | 99.290.110% | 1.07E+094.37E+074% | 0.680.1015% |
20%平均数STDevCV | 2.000.042% | 13.646.7950% | 5.35E+052.26E+044% | 99.610.060% | 1.07E+093.92E+074% | 0.410.0716% |
0%平均数STDevCV | 2.300.219% | 93.2866.0571% | 5.03E+034.96E+0210% | 98.230.260% | 1.00E+078.60E+059% | 1.930.3619% |
在表2中,STDev=标准偏差,CV=偏离系数,E+表示一定幂的指数,例如,5.45E+05=5.45×105。
简言之,已经发现稳定脂质体仅需少量的相对不溶的气体(如PFP),而绝大部分的气体是可溶性气体。虽然按下式:
(气体A的溶解度)×(气体A的摩尔百分数)+(气体B的溶液度)×(气体B的摩尔百分数)
100
计算的两种或两种以上的混合气体的有效溶解度与可溶性气体的溶解度仅有微小的差异,但仅加入少量的不溶性气体,仍有大量的气体填充的脂质体存在并且气体填充的脂质体的稳定性高。
虽然不受任何操作理论的束缚,人们相信基本上不溶的气体对于膜的稳定作用是重要的。事实上,人们相信基本上不溶的气体(如PFP)起到了脂质膜的屏障作用,可能有效地在膜的内表面形成层,阻止了可溶性气体(如空气、氮气等等)的向外逸出。这一发现既令人惊奇又十分有用,因为这使人们可仅用少量的基本上不溶的气体(如全氟化碳或其它氟化气体)和主要是生物相容性更好的(潜在毒性更小的)气体(如空气或氮气)来占据脂质体的大部分体积。
正如本领域的技术人员将认识到的,基本上不溶的气体和可溶气体在任何混合物中的量可在很宽的范围内变化。然而,基本上不溶的气体通常占气体总量的至少约0.01%,优选占至少约0.1%,更优选占至少约1%,并最优选占至少约10%。基本上不溶的气体的适当范围的变化取决于各种不同的因素如另外使用的可溶气体、类脂的类型、具体的应用等等。示例性的范围包括约0.01-99%、优选约1-95%、更优选约10-90%、并最优选约30-85%的基本上不溶的气体。
对于诊断超声显影以外的其它用途如诊断核磁共振显影(MRI),虽然也可使用其它气体,但优选使用顺磁气体如强顺磁气体氧17气体(17O2)、氖、氙(特别是富含铷的超极化氙气)或氧气(虽然氧气的顺磁性还不强)来填充液面上空间。氧17气体(17O2)、氖气、富含铷的超极化氙气或氧气最优选与基本上不溶的气体如全氟化碳气体混合。顺磁气体在本领域是已知的,适当的顺磁气体对于本领域的技术人员来讲是显然的。不管是单独使用还是与其它气体联合使用,对于MRI应用来讲最优选的气体是17O2。
通过使用混合气体,17O2或其它顺磁气体提供了最佳对比度并且全氟化碳稳定了振荡后被裹进气体中的17O2。在不加人全氟化碳气体的情况下,如17O2样的气体通常效果较差,因为它在静脉注射后由于它的溶解性而从类脂包被中扩散出来。另外,17O2气体很昂贵。将全氟化碳气体与17O2联合使用大大增加了产物的功效、并通过更有效地利用昂贵的17O2气体而使费用降低。其它具有所需顺磁性质的气体如氖气可同样地与全氟化碳气体混合。
如下面的表3所示,在MR显影中可使用各种不同的气体。表3示出了气体填充的脂质体中的不同气体的R2(1/T2/毫摩尔/升·秒-1)。如表3所示,不同气体填充的脂质体的应力松弛性差异极大,R2松弛值越高表明作为MR显影剂的脂质体越有效。在所示的气体中,空气具有最高的R2值。人们相信,空气的值最高是由于空气中氧气的顺磁效应。然而纯氧气却不那么有效,可能是由于氧气的溶解度较高和氧气进入脂质体周围含水环境中达到平衡而引起的。对于空气,氮气(空气的大约80%是氮气)有助于稳定脂质体中的氧气。氮气在水中的溶解性比空气小得多。如上所述,可将PFP或其它全氟化碳气体与磁活性较强的气体如空气、氧气、17O2或富含铷的超极化的氙气混合。这样,可制备出稳定的磁活性高的气体填充的脂质体。
表3
大小分布和松弛性
气体 | 数量权重分布(μm) | 体积权重分布(μm) | R1 |
氮气 | 6.96±0.63 | 31.08±7.42 | 474.6±59.9 |
六氟化硫 | 4.31±0.13 | 44.25±1.23 | 319.3±42.5 |
氙气(Rb) | 7.02±1.19 | 160.90±92.46 | 191.2±30.8 |
氩气 | 8.14±0.49 | 41.45±13.02 | 55.29±41.3 |
空气 | 6.05±1.05 | 23.28±0.41 | 1510.4±0.41 |
全氟丙烷 | 4.24±0.72 | 49.88±11.11 | 785±31.8 |
氧气 | 7.26±0.98 | 30.99±3.90 | 732.4±73.9 |
氖气 | 7.92±0.71 | 26.20±1.03 | 595.1±97.2 |
全氟丁烷 | 5.88±0.36 | 51.25±3.97 | 580.1±45.5 |
按需要,可在环境压力下、减压或加压下下将气体填充到容器的液面上空间。
在本发明的容器中,气相与类脂的含水悬浮液相是基本上分离的。术语“基本上分离的”是脂在振荡前,与含水类脂相混合的气体少于约50%。与含水类脂相混合的气体优选少于约40%、更优选少于约30%、还更优选少于约20%、并最优选少于约10%。使气相与含水类脂相基本上保持分离状态,直到使用的时候,使用时振荡容器,气相与含水类脂相混合形成气体填充的脂质体的水悬浮液。这种方式产生了用于超声或核磁共振显影的极佳的造影剂。而且,因造影剂是在使用之前刚刚制备的,减少了贮藏有效期稳定性的问题。
可以以各种方式进行振荡,所述方式包括机械和/或手动振荡,以及通过其它装置如超声(声波)进行振荡。机械和/或手动振荡是优选的。例如可通过振摇、搅拌、涡旋、振动等来进行振荡。可优选使用如图2所示的振荡装置。具体地讲,图2示出了机械振荡装置10。用开--关按钮11可启动和停止振荡。振荡装置10还包含旋钮12,该旋钮用于变速(RPM)的调节。向顺时针方向旋转旋钮12,振荡速度(以RPM表示)增加。反之,向反时针方反旋转旋钮12,振荡速度减小。通过将本发明的容器置于振荡装置10的调节架13之中可使容器中的内容物得到振荡。该调节架13起到了振荡装置10的振荡器的作用。为保证容器被牢固地置于调节架中以备振荡,使用了螺钉14。
本发明的容器可以采用各种不同的方式。如果需要,它可以是如图1所示的容器1,该容器1具有主体2和帽3,该容器内装有彼此基本上分离的液面上气体4和类脂的水悬浮液相5。另外,容器也可以采用预填注射器的形式,如果需要,注射器中可以填有一种或多种填料。在本发明中,注射器用含水相和预先选择的液面上气体填充。通常使注射器的长轴垂直于振摇方向将它们置于振摇装置中。振摇之后,在注射器里产生了气体填充的脂质体,备用。无论容器是如图1所示形式的容器、注射器还是其它类型的容器,容器及其内容物优选是灭菌的。
可用各种不同的材料如玻璃、硼硅酸盐玻璃、硅酸盐玻璃、聚乙烯、聚丙烯、聚四氟乙烯、聚丙烯酸酯类、聚苯烯或其它塑料来制造本发明的容器(包括注射器)。优选的容器(包括注射器)在填充气体前,是不透气的或是被不透气的外层屏障包裹的。当然,这是为了维持预先选择气体在容器中的整体性。具有气密性能的注射器材料的例子可包括(但无论如何不限于)玻璃硅酸酯或硼硅酸酯,适于二氧化硅融熔的注射器或钥(Luer)-锁型注射器、镶特氟隆的或特氟隆包被的柱塞。
本领域的技术人员应认识到,一旦掌握了本文公开的实质,可以向本发明的类脂含水悬浮液相中加入各种添加剂以稳定该相,或在振荡时稳定气体填充的脂质体。如需要,可将这些添加剂在振荡前加入到类脂含水相中,或在振荡及制备气体填充的脂质体之后加入到组合物中。当然,这类添加剂的使用依赖于所得气体填充的脂质体的具体应用,这一点对本技术领域的技术人员而言是显然的。
可以获得许多可用于本发明的稳定剂,包括xanthan树胶、阿拉伯树胶、琼脂、琼脂糖、藻酸、藻酸盐、藻酸钠、角叉莱胶、葡聚糖、糊精、明胶、瓜尔树胶、黄蓍胶、刺槐豆(胶)、黄蓍糖胶、刺梧桐树胶、阿拉伯树胶、果胶、酪蛋白、膨润土、末纯化的膨润土、纯化的膨润土、膨润土糊、胶态膨润土、纤维素、微晶纤维素微、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、羧甲基纤维素钠12、及其它天然的或修饰的天然纤维素、吐温、carbomer 934P、硅酸镁铝、单硬脂酸铝、聚环氧乙烷、聚乙烯醇、聚乙烯吡咯酮、聚乙二醇、丙二醇、聚乙烯吡咯烷酮、地氧化硅、胶态的二氧化硅、
而且,还可用全氟辛基溴(PFOB)、全氟辛基碘、全氟三丙基胺、和全氟三丁基胺之类的化合物作为类脂相的稳定剂。具有多于5个碳原子的全氟化碳通常在体温下为液态,而亦优选这样的全氟化碳作为稳定剂。合适的全氟化碳包括全氟己烷、全氟庚烷、全氟辛烷、全氟萘烷和十二氟代萘。此外,也可用全氟化的类脂或部分氟化的类脂以帮助稳定。本发明所描述的类脂的全氟化的或部分氟化的各种类似物均可使用,这一点对本领域的技术人员而言是显然的。由于烃类脂具有相对的疏水性质,这类全氟化的或部分氟化的类脂具有稳定的优点。全氟化的或部分氟化的类脂的例子是F6C11磷脂酰胆碱(PC)和F8C5PC。例如,这些类似物在Santaella等的Federation of European BiochemicalSocieties(FEBS)(《欧洲生化联合会》),336卷,第3期,418-484页(1993)中有描述,该文献公开的内容以其全部引入本文作参考。
为有助于稳定化的目的,也可使用各种生物相容性的油如花生油、Canola油、橄榄油、红花油、玉米油、杏仁油、棉籽油、桃仁油、芝麻油、大豆油、矿物油、矿物轻油、油酸乙酯、十四烷基醇、肉豆蔻酸异丙酯、棕榈酸异丙酯、辛基十二烷醇、丙二醇、甘油、角鲨烯或其它公知可被消化的油。这些物质也可包括卵磷脂、神经鞘磷脂、胆甾醇、胆甾醇硫酸酯和甘油三酯、
稳定化作用也可通过加入各种粘度改性剂(即粘度调节剂)来实现,这些粘度改性剂起本发明的稳定剂的作用。这类化合物包括(但无论如何不限于)1)糖类及其磷酸化和磺化的衍生物;2)分子量范围在400到8000的聚醚类;3)二和三羟基链烷烃和分子量范围在800到8000之间的它们的聚合物。脂质体也可与乳化剂和/或稳定剂结合使用,所述乳化剂和/或稳定剂包括(但无论如何不限于)阿拉伯树胶、胆甾醇、二乙醇胺、单硬脂酸甘油酯、羊毛脂醇、卵磷脂、甘油-酯和甘油二酯、单乙醇胺、油酸、油醇、poloxamer、硬脂酸-50-聚氧乙烯酯、聚烃氧基-35-蓖麻油、聚烃氧基-10-油基醚、聚烃氧基-20-鲸腊硬脂基(cetostearyl)醚、硬脂酸-40-聚烃氧基酯、吐温20、吐温40、吐温60、吐温80、丙二醇二乙酸酯、丙二醇单硬脂酸酯、月桂基硫酸钠、硬脂酸钠、脱水山梨醇单月桂酸酯、脱水山梨醇酯单油酸酯、脱水山梨醇单棕榈酸酯、脱水山梨醇单硬脂酸酯、硬脂酸、三乙醇胺、乳化腊、Pluronic F61、Pluronic F64和、Pluronic F68。
可加入的其它试剂包括滋补剂如多元醇(如甘油、丙二醇、聚乙烯醇、聚乙二醇、葡萄糖、甘露糖醇、山梨糖醇、氯化钠等)。
如需要,配方中也可包括抗菌剂和/或防腐剂。这类试剂包括苯甲酸钠、所有的季铵盐、叠氮化钠、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、山梨酸、山梨酸钾、山梨酸钠、抗坏血酸基棕榈酸酯(ascorbylpalmitate)、丁基化的羟基苯甲醚、丁化羟基甲苯、氯丁醇、脱氢乙酸、乙二胺四乙酸(EDTA)、单硫甘油、苯甲酸钾、偏亚硫酸氢钾、山梨酸钾、亚硫酸氢钠钾、二氧化硫和有机汞盐。
如果需要,可用渗透剂来控制渗透性。合适的有渗透活性的材料包括生理上相容的化合物如单糖、二糖、糖醇、氨基酸及各种合成的化合物。适当的单糖或糖醇包括,例如,赤藓糖、苏糖、核糖、阿拉伯糖、木糖、来苏糖、阿洛糖、阿卓糖、葡萄糖、甘露糖、艾杜糖、半乳糖、塔罗糖、海藻糖、核酮糖、果糖、山梨糖醇、甘露糖醇和景天庚酮糖,其中优选的单糖是果糖、甘露糖、木糖、阿拉伯糖、甘露醇和山梨糖醇。适当的二糖包括,例如,乳糖、庶糖、麦芽糖和纤维二糖。适当的氨基酸包括,例如,甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、天冬氨酸、谷氨酸、赖氨酸、精氨酸和组氨酸。合成的化合物包括,例如,甘油、丙二醇、聚丙二醇、乙二醇、聚乙二醇、和聚乙烯基吡咯烷酮。对于本领域的技术人员而言,其它适当的具渗透活性的各种材料是熟知的,这些材料也涵盖在本文所用的术语“渗透活性剂”的范围之内。
也可为各种不同的目的和用途加人如上面所讨论的那些各种聚合物。
本领域的技术人员应认识到,依据具体的最终用途,按需要或目的,可将大范围量的添加剂(如上面所述的悬浮剂)加入到本发明的类脂水悬浮液相中。所述的添加剂量虽然可更高或更低,但通常占所得造影剂配方的0.01%(体积)-95%(体积)。一般讲来,悬浮剂的量一般为至少约0.5%(体积),优选为至少约1%(体积)、更优选为至少约10%(体积)。悬浮剂的存在量通常少于约50%(体积)、优选少于约40%(体积)、更优选少于约30%(体积)。例如,悬浮剂的量一般为20%(体积)。而且,一般地,为达到通常优选的渗透性范围,使用的具渗透活性的材料的量为少于约25g/l,优选少于约20g/l,更优选少于约15g/l,还更优选少于约10g/l,而在某些情况不使用具渗透活性的材料。具渗透活性的材料的最优选的范围一般是约0.002g/l至10g/l。添加剂的这些及其它合适的范围,对于掌握了本发明的本领域的技术人员而言是显然的。
通过将所需的治疗或诊断试剂简单地加入到类脂水悬浮液相中,也可将各种不同的治疗和/或诊断试剂掺入到所述类脂相中。一旦本领域的技术人员掌握了公开的内容,适当的治疗和诊断试剂及其适当的量对于他们而言是显而易见的。这些试剂可被掺入到类脂膜内或膜上,或被包裹于所得脂质体中。
为进一步改善用于MRI的所得的气体填充脂质体的磁效应,例如,可加入一种或多种MRI造增强剂如顺磁或超顺磁造影增强剂。有用的MRI造影增强剂包括顺磁离子如过渡金属元素(包括铁(Fe+3)、铜(Cu+2)、和锰(Mn+2))、镧系元素如钆(Gd+3)和镝(Dy+3)、氧化氮、氧化铁(Fe3O4)、硫化铁和顺磁粒子如锰(Mn+2)取代的羟基磷灰石。而且,铬(Cr+3)、镍(Ni+2)、钴(Co+2)和铕(Eu+2)是其它可以使用的顺磁离子的例子。也可使用其它造影增强剂如氧化氮自由基或任何其它带有未成对自旋电子、有顺磁性的原子。虽然在脂质体制备后加入造影增强剂也是可行的,但理想的是在振荡前将之加入到类脂水悬浮液相中,这样可使造影增强剂在振荡后掺入到所得的气体填充的脂质体的表面之中或之上。所得的气体填充的脂质体具有大大提高了的松弛性,是核磁共振显影的极为有效的造影剂。例如,当在含水类脂相中使用了磷脂酰胆碱或磷脂酰丝氨酸时,锰(Mn+2)将掺入到类脂的头部基团上。如果需要,可用例如在Unger等的美国专利No.5,312,617中所述的脂溶性化合物螯合该金属,Unger的专利No.5,312,617以其全文公开的内容引入本文作参考。因为所述的脂溶性化合物易于掺入到脂质体膜中,它们非常有用。为使氧化铁和其它颗粒掺入到脂质体膜之中或之上的效果达到最佳,它们通常应较小,优选小于约1μm,更优选小于约200nm,最优选小于约100nm。为改善掺入情况,可使用由脂肪族化合物或亲脂化合物包被的氧化铁,因为脂肪族或亲脂化合物本身易于掺入到泡沫表面的类脂层中。
在类脂的水悬浮液相中含有可引起不能自发地产生凝胶的类脂聚合物和金属产生凝胶作用或增强凝胶作用的组分,也在本发明的范围之内。可使用一胶凝剂如多价金属阳离子、糖和多元醇。用作凝胶剂的多价金属阳离子包括钙、锌、锰、铁和镁。有用的糖包括单糖如葡萄糖、半乳糖、果糖、阿拉伯糖、阿洛糖和阿卓糖;二糖如麦芽糖、蔗糖、纤维二糖和乳糖;和多糖如淀粉。糖优选简单的糖,即单糖或二糖。可用于本发明的多元醇胶凝剂包括,例如,缩水甘油、肌醇、甘露糖醇、山梨糖醇、季戊四醇、galacitol和聚乙烯醇。用于本发明的胶凝剂最优选庶糖和/或钙。本领域的技术人员一旦掌握了本文公开的内容,对他们而言可用于本发明各种配方的具体的胶凝剂是显而易见的。可将类脂如磷脂酸与钙盐或镁盐以及聚合物如藻酸、透明质酸或羧甲基纤维素混合,用以稳定类脂。据推测,在类脂/聚合物系统内二价阳离子在类脂和聚合物之间形成金属键,稳定气体填充的脂质体。可类似地制备含有脱乙酰几丁质(或基于几丁质的物质)、聚赖氨酸、聚乙烯亚胺和藻酸(或其衍生物)或透明质酸的混合物的悬浮液。
已经发现振荡的速率、含水类脂相中类脂的量、以及密闭容器的大小均会影响任何气体填充的脂质体的最终大小。另外,已经发现这类试剂的比例对于气体填充的脂质体的大小分布也很重要。当与振摇速率、管形瓶大小和类脂浓度一起考虑时,人们相信气体填充的脂质体介面与含水环境间的表面张力是决定气体填充的脂质体最终大小的另一个决定因素。
在装有含水相和液面上气体的无菌容器中,已经发现了怎样进行简单方便的变化以改变振摇后脂质体的大小,从而获得具有所需大小分布的脂质体产品。此外,还可进行过滤以进一步细化振摇后的造影剂的大小分布。下文回顾了怎样改变本发明的组分以调整脂质体的大小。
首先,已经发现含水相中不同的材料对于控制所得气体填充的脂质体的大小是重要的。表4列出了通过振摇装有含水相和液面上的氮气的无菌容器而产生的脂质体的大小。在所有的情况下,脂质体的大小均由Particle Sizing System 770型不可见光颗粒大小测定仪(Particle SizingSystems,Santa Barbara,CA)测定。如数据所示,在含水相中的类脂的比率影响所得的气体填充的脂质体的大小分布。具体地讲,下表4列出了类脂组合物对脂质体平均大小的影响。
表4
类脂组合物对脂质体平均大小的影响
类脂组合物* | 脂质体平均大小 |
77.5∶15∶7.5 | 5.26μm |
77.5∶20∶2.5 | 7.33μm |
82∶10∶8 | 6.02μm |
*二棕榈酰磷脂酰胆碱∶二棕榈酰磷脂酸∶二棕榈酰磷脂酰乙醇胺-PEG5000的比率,以mole%表示。
表5显示了脂质体平均大小对特定类脂组合物混合物的浓度的依赖。如表5所示,类脂总浓度的变化对于影响振摇后的脂质体大小也是重要的。在这些试验中,三种不同类脂组分的比率保持衡定,而在含水相中类脂的浓度在0.5-50mgml-1之间变化。所用的气体是氮气。当含水相中的类脂浓度为1.0mgml-1时,用液面上的全氟丁烷产生了用于超声诊断的最佳大小的气泡。
表5
类脂浓度对脂质体平均大小的影响
类脂浓度* | 脂质体平均大小 |
1mgml-1 | 1.8μm |
3mgml-1 | 4.0μm |
5mgml-1 | 7.2μm |
*对于所有的样品,类脂的浓度均基于mole%,二棕榈酰磷脂酰胆碱∶二棕榈酰磷脂酸、二棕榈酰乙醇胺-PEG5000的比率为82∶10∶8。所用的气体为氮气。
脂质体的大小除了依赖于稳定化介质(即类脂)的浓度外,还依赖于液面上气体的组成。例如,已经发现当使用氮气时,1.0mgml-1的类脂浓度产生的气体填充的脂质体的直径大小与使用全氟丁烷时5.0mgm-1的类脂浓度产生的大小大体相等。然而,已经发现较高的浓度可导致分布更偏向于形成较大的气体填充的脂质体。这种现象反映了在类脂浓度较高时,气体填充的脂质体的稳定性增加了。因此,人们相信较高的类脂浓度或者由于起到含水相中稳定剂的作用而有助于稳定性的提高,或者在气体周围产生更多的薄层,使它们更稳定,并因此使较高比例的较大的脂质体存在下来。另外还发现,也可用液面上气体体积的大小来影响气体填充的脂质体的大小。相对于含水相的体积而言,较大的液面上空间含有成比例地更多的气体,较大的液面上空间通常比较小的液面上空间产生的脂质体大。
振荡速度对于产生适当大小的脂质体来讲是重要的。已经发现在100-10,000转/分(RPMs)的振荡速度可用于制备脂质体,然而,在快速地和可重复地产生特定大小的脂质体方面仍有最佳值。本文所用的术语“一转”是指一次前后、上下、一边到另一边、环状的运动,该运动开始于和终止于(即返回到)原点。表3显示由82%(摩尔)的二棕榈酰磷脂酰胆碱(DPPC)、10%(摩尔)的二棕榈酰磷脂酸(DPPA)和8%(摩尔)的二棕榈酰磷脂酰乙醇胺-PEG5000(DPPE-PEG5000)组成的含水相和含全氟丙烷的液面上气体产生的脂质体的大小。将制剂在Wig-L-BugTm(Crescent Dental Mfg.,Lyons,Ill.)上振摇2分钟。用装有含水类脂相和液面上气体的2ml的琥珀色管形瓶(Wheaton Industries,Millville,NJ;实际体积为3.7ml),将本发明的多相容器置于Wig-L-Bug Tm之上,以Co-Palmer Model 08210 Pistol Grip转速表(Code-Palmer,Nile,Ill.)测速度。表6列出了结果,并表明了振荡速度对所得的脂质体平均大小的影响。
表6
振荡速率对脂质体平均大小的影响
速度(RPM) | 脂质体的平均大小 |
1500 | 3.4μm |
2800 | 3.3μm |
3300 | 2.9μm |
确实,已经发现存在着产生所需大小的脂质体的最佳振荡速度。在最佳速度时,气体填充的脂质体的形成非常快,在不到5分钟内、甚至在一两分钟内、更甚至在30秒或更少的时间内形成。注意到振摇的方法和动作对于形成适当大小的脂质体是十分重要的。具体地讲,已经发现当振摇的往复动作以弧形进行时,形成最佳大小的脂质体。动作的弧度优选为2°-20°。动作的弧度范围更优选为4°-10°。动作的弧度范围还更优选为5°-8°。动作的弧度范围最优选为6°-7°。在本发明的另一实施方案中,已经发现RPM的值优选在约500-约10,000之间,更优选在约1000-约5000之间,并最优选在约2500-约4000之间。
本发明的另一个重要的发现是振荡液体物质时获得的液面上气体的体积的大小、形状、和数量对于形成最佳大小的气体填充的脂质体亦是至关重要的。例如,本发明发现当使用实际体积为3.7ml的管形瓶(Wheaton 300硼硅玻璃,Wheaton Industries,Millville,NJ,称为2ml大小,直径×高=15mm×32mm)时,含气体的液面上空间的体积优选占管形瓶总体积的约10%-约60%。虽然根据具体的环境和应用目的,更多或更少的气体也许更为合适,但管形瓶内含气体的液面上空间通常占该管形瓶总体积的约10%至约80%。液面上空间更优选占总体积的约30%至约70%。含气体的液面上空间的体积通常最优选占管形瓶总体积的约60%。
因此,从上面对本发明的讨论中可以清楚地看出最佳大小的产生依赖于各种因素,包括振荡的强度及动作、管形瓶的大小、形状以及实际的填充体积。
虽然可以使用各种不同的振荡装置来制备气体填充的脂质体,例如使用涂料混合器、桌面振摇器和涡旋机,但振摇的几何形状和速度对于使气体填充的脂质体的形成最佳化是重要的。Wig-L-Bug Tm是最优选的振荡装置。
无菌容器的大小、容器的几何形状以及容器相对于振摇装置的定向,在决定气体填充的脂质体的大小方面是重要的。当无菌容器的重量超过一定值时,振摇装置(如,Wig-L-Bug Tm)通常振摇得较慢。标准的Wig-L-Bug Tm对2ml管形瓶(实际体积为3.7ml)比10ml的管形瓶振摇得快。该试验使用10ml透明的管形瓶(Wheaton Industries,Millville,New Jersey)和2ml(实际体积为3.7ml)琥珀色管形瓶(WheatonIndustries,Millville,New Jersey)。再次Code-Palmer Pistol Grip转速计(Code-Palmer,Nile,Ill.)测振摇速率。结果列于表7。
表7显示了电动振荡器的振摇速率对进行振摇所用的管形瓶大小的依赖关系。
表7
管形瓶大小对Wig-L-Bug Tm振摇速率的影响
管形瓶大小 | 测得的速率 |
2ml管形瓶 | 3250 |
10ml管形瓶 | 2950 |
一般说来,以无菌容器来实践本发明,所述容器中已有含水相存在。然而对于选定的应用,可将稳定介质以干燥的或冻干的状态贮存于容器中。在此情况下,含水的溶液(如,无菌磷酸盐缓冲液)是在振摇前才加入到无菌容器中的。这样一来,在含水相中再水化的稳定介质再次在摇过程中与液面上气体相互作用,从而产生上述的气体填充的脂质体。干燥的或冻干的悬浮介质的再水化必然进一步使产物变得复杂,这一般是人们所不希望的,但对于进一步延长某些制剂的贮藏期却是有用的。例如,某些治疗剂如环磷酰胺、多肽和遗传物质(如DNA)长期在含水环境中贮存可能会被水解。将预先冻干的样品在振摇前再水化形成含水相和液面上空间,可以制备含有化合物的气体填充的脂质体,否则这些化合物不可能会有足够长的贮藏期。
上文列出了决定气体填充的脂质体大小的各种参数。脂质体大小在使产物的功效最大和毒性最小方面是重要的。另外,脂质体应尽可能地柔韧,以使功效最大并使对组织的副作用如在肺中的滞留时间最小。本发明可产生具有极薄的柔韧膜的所需大小的脂质体。因为脂质体的膜是极薄并有柔韧性的(例如只需1mgml-1的类脂以稳定该膜),已经发现可使用较大直径的气体填充的脂质体而不产生肺动脉高血压。例如,对猪给予5倍于诊断显影所需剂量的剂量,而没有任何肺动脉高血压的征兆。相反,很低剂量的较小直径的白蛋白包被的空气泡在这些动物中引起严重的肺动脉高血压。因为本发明的脂质体是十分柔韧和可改变形状的,它们易于在肺毛细血管内滑过。另外,用于本发明类脂(例如带有聚乙二醇的类脂)的包被技术使肺部的副作用减小并同时使产品在体内、体外的稳定性和功效提高。
由于当频率使气体填充的脂质体在Rayleigh散射范围时,其反向散射或超声效应与半径的6次方成正比,用作普通超声造影剂的气体填充的脂质体的大小应尽可能地大(在不引起栓塞效应的情况下)。对于MRI,也优选较大的本发明的脂质体。本发明的制备和应用潜在的毒性效应较低的较大脂质体的能力,使其相对于其它产品的效能增加了。
影响超声对比的另外的参数是脂质体膜的弹性。弹性越大,对比效果越强。因为本脂质体是由超薄的类脂膜包被的,其弹性与裸气的弹性十分相近,而且反射性和对比效果是最大的。
本发明的振荡步骤易于在无菌容器内从含水相和液面上气体中产生脂质体。本发明足以产生用于超声或核磁共振显影的具有极需性质的脂质体。然而对于选定的应用,可用滤器来产生大小分布更为均匀的具有所需直径的脂质体。例如,为了使用气体填充的脂质体的谐振现象在体内测量对超声的压力,使脂质体的直径非常固定地限定在极窄的大小范围是有用的。这一点可通过将脂质体(通过振摇装有含水相和液面上气体的容器而产生)注射通过特定大小的滤器容易地完成。所得的脂质体不大于极接近于滤膜上滤孔大小的近似值。如上所述,对于许多超声或MRI应用,需要使气体填充的脂质体尽可能地大。然而对于某些应用,需要更小的气体填充的脂质体。例如,在靶向肿瘤或其它疾病组织时,必须使气体填充的脂质体离开血管而进入组织间隙中。更小的气体填充的脂质体可用于这些应用。可通过改变含水相中的化合物(改变组成和浓度)及改变液面上气体(气体组成及液面上体积),或者通过使之注射通过滤器来很大程度地产生这些较小的气体填充的脂质体(例如,最好直径在1μm以下)。将脂质体注射通过例如0.22μm的滤器,可产生大小基本上均匀的极小的气体填充的脂质体。所得的纳米大小的气体填充的脂质体可具有用于靶向的性质。
上述类脂悬浮液的实例也可用高压灭菌器使之灭菌,而悬浮液的体积无可察觉的变化。可用高压灭菌器和/或通过无菌过滤在振荡步骤之前或之后,或通过本领域的技术人员已知的其它方式对造影剂进行灭菌。
在容器中装入了含水相和预先选择的液面上气体后,密闭的瓶子可无限期地贮存。不会有颗粒沉淀出来,不会有气体填充的脂质体爆发出来,在气体填充的脂质体、颗粒、胶体或乳剂之间也不会有非定向的相互作用。装有含水相和液面上气体的容器的贮存期依赖于含水相中所含化合物的稳定性。长的贮存期及可消毒性这些性质使本发明比现有技术有明显的优越性。本文已经述及了稳定性的问题,如超声造影剂领域中普遍存在的聚集和颗粒沉淀现象。
已经发现通过振荡本发明的多相容器产生的气体填充的脂质体,具有作为诊断显影如超声或核磁共振显影的造影剂的极好的实用性。该脂质体通常可用于患者的显影、和/或特异地诊断患者的患病组织的存在。通过对患者施用本发明的气体填充的脂质体,然后用超声或核磁共振对患者扫描以获得患者体内区域和/或该区域内的任何患病组织的可见图像,来进行显影过程。术语“患者区域”是指整个患者、或患者的特定区域或部分区域。脂质体造影剂可用于产生脉管系统、心脏、肝脏和脾的图像,以及胃肠腔区域或其它体腔的显影,或以对本领域的技术人员而言显而易见的其它方式用于,例如,组织鉴定、郁血显影等等。在本发明的实践中可以使用各种不同类型的超声或核磁共振显影装置,装置的具体类型或型号对于本发明的方法而言是不重要的。
正如本领域的技术人员可以认识到的,亦可用本发明的气体填充的脂质体向患者传递各种治疗剂以进行各种疾病或病痛的治疗。
而且,可用磁活性的脂质体通过MRI估测压力。脂质体使体积感受性增加,并因此使T2松驰增加,但更使T2 *松驰增加。因为静电场梯度效应主要由自旋回旋试验(根据180°射频再聚焦脉冲进行)补偿,当静电场效应未被补偿时,脂质体对T2的效应不如对T2 *加权脉冲序列的效应显著。压力的增加导致脂质体的损失或脂质体的破裂(对于更易溶的气体而言),并导致脂质体直径的减小。因此,1/T2随着压力的增加而减小。而压力释放后,剩下的一些脂质体再度膨胀,1/T2再次略微增高。随着压力的变化,由约80%PFP和20%空气组成的脂质体的稳定性提高,1/T2略有下降,所述压力在压力释放后返回到基线上(也就是说,脂质体是稳定的,但略微显示出1/T2压力效应)。当得到了梯度回波图像并测定了信号强度时,这些效应更为显著。随着压力的增加,信号强度增加(1/T2 *随着压力的增加而减小)。因为试验进行得相对较快(进行梯度回波图像显影所花的时间比测T2所花时间的十分之一还少)。暴露于压力的期间少得多,并且在压力释放后,氮气填充的脂质体几乎返回到基线(即,脂质体几乎没有损失)。因此,压力返回到环境压力时,对梯度回波的信号强度几乎降回到基线。对于通过MRI进行的压力测量,可以将脂质体设计成或者随着压力的增加而破裂,或者是稳定的,但随着压力的增加脂质体的直径减小。因为在MRI中脂质体的半径影响1/T2 *,可用该关系通过MRI估测压力。
正如本领域的技术人员所能认识到的,以各种方式如通过静脉内或动脉内注射、口服或直肠对患者进行气体填充的脂质体的给药。给药的剂量和给药的具体方式将取决于年龄、体重和具体的哺乳动物以及要被扫描或治疗的区域、所使用的具体的造影剂或治疗剂。一般,起始剂量较低,逐渐增加直到达到所需的对比增强或治疗效果。患者可以是任何类型的哺乳动物,但人是最优选的。
意欲以下列实施例来描述本发明是怎样被利用的以及本发明的一些超凡的用途。这些实施例仅是示例性的,并不应看成是对所附权利要求的限制。
实施例
实施例1
氮气填充的脂质体的形成
在2只20ml的管形瓶中,以含有正常(生理)盐水∶丙二醇∶甘油(8∶1∶1,体积比)的6ml稀释液制备气体填充的类脂双层。向该瓶中加入摩尔百分比为82∶10∶8(mole%)的二棕榈酰磷脂酰胆碱(DPPC):二棕榈酰磷脂酸(DPPA):二棕榈酰磷脂酰乙醇胺-PEG5000(DPPE-PEG5000)的混合物,使其终浓度为5mgml-1。然后用气密的可维持压力的隔膜帽使样品密封。然后用氮气(99.98%,Arizona Welding Co.,Tueson,AZ)对它们至少清扫(Purged and evacuated)3次。接着将样品在BarnsteadC57835型蒸气灭菌锅(Barnstead/Thermolyne Corporation,Dubuque,Iowa)中于120℃高压灭菌15分钟,或者使之通过0.22μm的Nuclepore滤器(Costar,Pleasanton,CA)进行无菌过滤一到三次。然后将样品从高压锅中取出,使之冷却至接近于环境温度。接着使样品在Wig-L-Bug涡旋机(Crescent Dental Mfg.Co.,Lyons,IL)上涡旋2分钟。所得的混合物显示有明显的气体填充的双层(看起来象泡沫)形成。在PatideSizing Systems 770型不可见光探测仪(Partile Sizing Systems,SantaBarbara,CA)上、在装有校准目镜的Reichert-Jung150型光学显微镜(Cambridge Instruments,Buffalo,NY)上、和在Coulter Model(CoulterIndustries,Luton Beds,England)上,以三种方法测量气体填充的类脂双层的大小。样品的数量加权平均大小为5-7μm,其中有至少95%的颗粒小于10μm。
实施例2
全氟戊烷气体填充的脂质体的形成
在2只20ml的管形瓶中,以含有正常(生理)盐水∶丙二醇∶甘油(8∶1∶1,体积比)的6ml的稀释液制备气体填充的类脂双层。向该瓶中加入摩尔百分比为82∶10∶8(mole%)的二棕榈酰磷脂酰胆碱(DPPC)∶二棕榈酰磷脂酸(DPPA)∶二棕榈酰磷脂酰乙醇胺-PEG5000(DPPE-PEG5000的混合物,使终浓度在1mgml-1至5mgml-1之间变化。向该混合物中加入50μl(30.1μmole)的全氟戊烷(PCR,Gainesville,FL)。在-20℃下制备样品,并用气密的和可维持压力的隔膜帽密封样品。接着将样品在Bamstead C57835型蒸气灭菌锅(Bamstead/Thermalyne Corporation,Dubuque,Iowa)中于120℃高压灭菌15分钟。然后从高压锅中取出样品,并使之冷却至接近40℃。接着使样品在Wig-L-BugTm涡旋机(Crescent Dental Mfg.Co.,Lyons,IL)上涡旋2分钟。所得的混合物显示有明显的气体填充的双层(看起来象泡沫)形成。记录泡沫的体积和高度,将一份样品置于-20℃冷冻箱(KenmoreBrand,Sears-Roebuck,Chicago,IL)中。3个小时后取出样品,此时注意到原始体积的近90%保留下来。将样品在冷冻箱中放置过夜(约17个小时),取出,此时发现原始体积的50%保留了下来。余下的管形瓶用作对照,使之保存于30℃的温箱中达同样的时间。发现没有发生体积损失,这表明冷却使气体填充的双层内的气体收缩,因此气体的体积减小了。最后,将冷样品置于30℃的温箱中,发现过了大约45分钟之后,有20%的原始泡沫体积得以恢复。这表明压缩的气体再次挥发使气体填充的脂质体的大小膨胀这一事实。
实施例3
全氟丙烷气体填充的脂质体的形成
除了所用的气体是全氟丙烷(99.99%,Alcon Surgical,FortWorth,TX)和所用的管形瓶的大小为2ml琥珀色管形瓶(实际体积为3.7ml)(Wheaton,Millville,NJ)外,采用与实施例1中所用的相同的步骤。管形瓶中装有1.5ml的类脂/稀释剂载体混合物。用与实施例1中的方法相同的方法测大小,然而这次产生的大小为4-6μm,而多95%颗粒小于10μm。
实施例4
全氟丁烷气体填充的脂质体的形成
除了所用的气体是全氟丁烷(97+%,Flura Corporation,Nashville,TN)和所用的管形瓶的大小为2ml琥珀色管形瓶(实际体积为3.7ml)(Wheaton,Millville,NJ)外,采用与实施例1中所用的相同的步骤。管形瓶中装有1.5ml的类脂/稀释剂载体混合物。用与实施例1中的方法相同的方法测大小,然而这次产生的大小为4-6μm,而多于95%的颗粒小于10μm。
实施例5
全氟环丁烷气体填充的脂质体的形成
除了所用的气体是全氟环丁烷(99.8%,Pfaltz & Bauer,Waterbury,Conneticut)和所用的管形瓶的大小为2ml琥珀色管形瓶(实际体积为3.7ml)(Wheaton,Millville,NJ)外,采用与实施例1中所用的相同的步骤。管形瓶中装有1.5ml的类脂/稀释剂载体混合物。用与实施例1中的方法相同的方法测大小,然而这次产生的大小为4-6μm,而多于95%的颗粒小于10μm。
实施例6
六氟化硫气体填充的脂质体的形成
除了所用的气体是六氟化硫(99.99%,Alcon Surgical,Fort Worth,TX)和所用的管形瓶的大小为2ml琥珀色管形瓶(实际体积为3.7ml)(Wheaton,Millville,NJ)外,采用与实施例1中所用的相同的步骤。管形瓶中装有1.5ml的类脂/稀释剂载体混合物。用与实施例1中的方法相同的方法测大小,然而这次产生的大小为4-6μm,而多于95%的颗粒小于10μm。
实施例7
使用体外声频衰减试验全氟丁烷气体
填充的脂质体在压力下的稳定性
如实施例4所述,形成全氟丁烷气体填充的类脂双层。将类脂浓度在1mgml-1-5mgml-1间变化的样品分成200μl的等份,用生理盐水作稀释剂进行10,000∶1的稀释。开始用磁力搅拌器混合样品,以产生均匀性,然后关闭。使用不锈钢盘作为极好的反射器,将之安置于离转换器的起点约25cm之处。所用的转换器是5.0MHz宽谱带非聚焦浸没式转换器(Panametries,Waltham MA)。所有的数据均经488.2GPIB板(National Instruments,Austin,TX)传递,并由Gateway 200080486处理器处理。
在对气体填充的类脂双层取样之前,基线对照仅在生理盐水中进行测量。在对照条件建立之后,立即将200μl的等份加入到盐水溶液中,并使数据在环境温度下(20℃)积累90秒。声波的衰减在90秒内保持恒定(参见图4),衰减率为2.0±0.5dBcm-1。将样品的压力升高到120mmHg,得到了第二个样品,并记录下衰减。如同在环境温度试验中一样,衰减保持恒定,在90秒的试验期间几乎没有变化,然而衰减率约为0.9dBcm-1。然后在37℃的恒温条件下对另一样品进行测定。在90秒的期间内,衰减再交保持恒定,且衰减率约为0.9dbcm-1。终样品在37℃、120mmHg的压力下进行测量。此次衰减在90秒内以线性的方式从0.9dBcm-1随时间衰减到0.4dBcm-1。这证明了该配方较氮气填充的类脂双层的稳定性有所增高。
实施例8
使用体外声频衰减试验氮气填充的脂质体在压力下的稳定性
除了气体填充的类脂双层含有如实施例1中所描述的氮气外,进行如实施例7同样的试验。在环境温度(20℃)和人体温(37℃)下稳定衰减,衰减率很明显,然而当稀释的内容暴露于120mmHg压力时,衰减立即下降到接近于基线对照值。这证明与全氟丁烷填充的类脂双层相比,在压力下氮气填充的类脂双层缺乏稳定性。
实施例9
类脂的浓度对全氟环丁烷气体填充的
脂质体的数量加权平均大小的影响
除了3种不同的类脂配方浓度外,如实施例5所述制备全氟环丁烷气体填充的类脂双层。配方内含有稀释剂,所述稀释剂含有正常(生理)盐水∶丙二醇∶甘油(8∶1∶1,体积比)。向其中加入二棕榈酰磷脂酰胆碱(DPPC)∶二棕榈酰磷脂酸(DPPA)∶二棕榈酰磷脂酰乙醇胺-PEG5000(DPPE-PEG5000)为82∶10∶8(mole%)摩尔比的混合物,使之终浓度在1mgml-1-5mgml-1之间变化。样品在2ml管形瓶(实际体积=3.7ml)(Wheaton Industries,Millville,NJ)内制备,以Particle SizingSystems Model 770不可见光大小测定系统测大小。下表列出了结果。
表9以全氟环丁烷为例,表明了类脂浓度对全氟化碳气体填充的类脂双层平均大小的影响。
表9
类脂浓度对全氟环丁烷气体填充的脂质体的影响
类脂浓度 | 数量加权平均大小 |
1.0mgml-1 | 3.1μm |
3.0mgml-1 | 3.8μm |
5.0mgml-1 | 4.7μm |
实施例10
使用基本上不溶的气体填充的
脂质体显示血液动力学改变的缺乏
用全氟丙烷(PFP)、全氟环丁烷(PFCB)、全氟丁烷(PFB)和六氟化硫(SHF),以1mgml-1和3mgml-1类脂的总类脂浓度制备含有如实施例3、4、5和6中所述的含有类脂混合物的气体填充的类脂双层样品。用装有5兆赫兹转换器的5200s型Acoustic Imaging超声仪,在重量为约28kg的Mongrel狗中进行显影。该动物以戊巴比妥钠镇定,用室内空气进行换气,并监测其肺动脉血压、系统动脉血压和脉搏次数。在短轴位置对心脏进行显影,使动物接受剂量为每千克5ml的PFP、PFCB、PFB和SHF丸剂,每种均测验1mgml-1和3mgml-1的类脂浓度。每次注射应间隔至少15分钟,以清除任何残留的造影剂。在所有的全氟化碳填充的脂质体(PFP、PFCB和PFB)中,1mgml-1的类脂显示心肌灌注增加,但PFB比其它的类脂的作用更强。PFP在3mgml-1时作用提高。SHF填充的脂质体在类脂为1mg/ml时,不显洋心肌灌注增强,但当类脂为3mg/ml时,却显示明显的心肌增强。
在另一只狗身上基本上重复上述试验并得到了相同的结果。
用全氟丙烷填充的脂质体在另一只狗身上进行了血液动力学研究。该动物按接受高至300微升/千克(即,高于显影剂量的50倍)的多剂快速丸。尽管是多剂量,该动物在血液动力学参数方面绝对未显示出任何变化,表明该药物有高度的血液动力学安全性。
实施例11
基于Balb/c小鼠的毒性试验确定治疗比
用重约20-25克的Balb/c小鼠进行毒性试验。通过快速胶丸测定包裹有全氟丙烷(PFP)、全氟环丁烷(PFCB)、全氟丁烷(PFB)、和六氟化硫(SHF)的类脂浓度为1mgml-1的脂质体的LD50。PFCB、PFB和PFP各样品的LD50均大于12ml/kg,而对于SHF气体填充的类脂双层,大于30mgkg-1,这表明可用于超声诊断的这些产品的治疗指数分别大于2400∶和6000∶1.
实施例12
全氟戊烷气体填充的脂质体用作超声造影剂
给新西兰白兔肌肉注射1cckg-1的Rabbit Mix(8∶5∶2,体积比,甲苯噻嗪(20mgml-1)∶氯胺酮(10mgml-1)∶乙酰丙嗪(100mgml-1)使之麻醉。兔子在Acoustic Imaging Model 5200诊断超声仪及Acoustic ImagingMoclel5200s诊断彩色多普勒仪(Acoustic Imaging,Phoenix,AZ)上显像。用23G蝶形导管通过耳缘静脉对兔子进行注射。在5-10秒钟内对兔子给予剂量为0.01cckg-1-O.1cckg-1的全氟戊烷填充的类脂双层在20分钟到超过1小时的时间范围内,用7.5MH2的转换器在长轴方向上显示出心脏的全部四个室和心肌的鲜艳图像。然后将转换器移到肝区,在此处观察到了肝静脉、肝门静脉以及肝窦的对比鲜明图像。然后将转换器移到肾脏,显示出髓质区和皮质区的明显差别以及肾动脉的图像。然后用彩色多普勒仪替换超声诊断转换器,观察到了动物体的所有血管化组织的持久鲜明的对比。
实施例13
不同的全氟丙烷和空气浓度对气体填充
的脂质体的数目和大小的影响
将2ml管形瓶(实际体积为3.7ml)(Whenton Industries,Millville,NJ)内的溶于生理盐水∶甘油∶丙二醇为8∶1∶1(重量比)的类脂溶液(每毫升1毫克,PPPC∶DPPA∶DPPE-PEG-5000为82∶10∶8mole%)的样品置于容积为4立方英尺的改进了的Edwards Model S04冻干器上,并进行减压。对管形瓶的液面上空间充以80%PFP和20%空气、60%PFP和40%空气、50%PFP和50%空气、20%PFP和80%空气、或100%空气。不同样品的液面上空间内的气体百分含量用带有HewlettPackard ChemTm软件的1050L型惠普气相色谱仪进行的气相色谱证实。检测的方式是火焰电离检测。然后用Wig-L-Bug Tm使样品以3,300RPM振摇60秒,如前所述用光学颗粒大小测定法测定质脂体的大小和数目。所得结果列于表2。
本文所引用的每篇专利和文献公开的内容均以其全部引入本文作参考。
对于本领域的技术人员而言,从前面的描述中,除了本文所述和所示的那些外,显然可对本发明进行各种改进。这些改进也将落入所附权利要求的范围之内。
Claims (25)
1.一种密封的容器,其内容物为含有类脂的水悬浮液相和含有基本上不溶性气体的液面上气相,其中在使用前震摇所述容器后该容器产生用作造影剂的气体填充的脂质体。
2.权利要求1的密封的容器,其中所述基本上不溶性气体选自六氟化硫、全氟丙烷、全氟丁烷、全氟环丁烷、全氟甲烷、全氟乙烷和全氟戊烷。
3.权利要求2的密封的容器,其中所述基本上不溶性气体选自全氟丙烷和全氟丁烷。
4.权利要求3的密封的容器,其中所述的基本上不溶性气体是全氟丙烷。
5.权利要求1的密封的容器,其中还含有选自空气、氧气、二氧化碳和氮气的可溶性气体。
6.权利要求1的密封的容器,其中所述的类脂包括选自二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酸、二棕榈酰磷脂酰乙醇胺的磷脂。
7.权利要求1的密封的容器,其中所述的水悬浮液相还包含靶向配体。
8.权利要求7的密封的容器,其中所述的靶向配体是聚乙二醇。
9.权利要求1的密封的容器,其中所述的水悬浮液相包含二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酸、二棕榈酰磷脂酰乙醇胺-PEG5000。
10.权利要求9的密封的容器,其中所述的水悬浮液相包含选自二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酸、二棕榈酰磷脂酰乙醇胺-PEG5000,其摩尔百分比为82%∶10%∶8%。
11.权利要求1的密封的容器,其中所述的水悬浮液相还含有悬浮剂。
12.权利要求1的密封的容器,其中所述的水悬浮液相还含有粘度调节剂。
13.权利要求12的密封的容器,其中所述的粘度调节剂选自甘油、丙二醇和聚乙烯醇。
14.权利要求1的密封的容器,其中所述的水悬浮液相还含有治疗或诊断剂。
15.权利要求14的密封的容器,其中所述的诊断剂是核磁共振显影造影增强剂。
16.权利要求15的密封的容器,其中所述的核磁共振显影造影增强剂是顺磁离子。
17.权利要求1的密封的容器,其中所述的容器是无菌的。
18.气体填充的脂质体,其包含基本上不溶性气体和可溶性气体。
19.权利要求18的气体填充的脂质体,其中所述的基本上不溶性气体选自六氟化硫、全氟丙烷、全氟丁烷、全氟环丁烷、全氟甲烷、全氟乙烷和全氟戊烷。
20.权利要求19的气体填充的脂质体,其中所述基本上不溶性气体选自全氟丙烷和全氟丁烷。
21.权利要求20的气体填充的脂质体,其中所述的基本上不溶性气体是全氟丙烷。
22.权利要求18-21中任一项所述的气体填充的脂质体,其中所述的可溶性气体选自选自空气、氧气、二氧化碳和氮气。
23.权利要求18-21中任一项所述的气体填充的脂质体,其中所述的脂质体包括一层类脂单层。
24.权利要求18-21中任一项所述的气体填充的脂质体,其中所述的脂质体包括一层类脂双层。
25.权利要求18-21中任一项所述的气体填充的脂质体,其中所述的脂质体包括两层以上的类脂层。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/307,305 US5773024A (en) | 1989-12-22 | 1994-09-16 | Container with multi-phase composition for use in diagnostic and therapeutic applications |
US08/307,305 | 1994-09-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1158082A CN1158082A (zh) | 1997-08-27 |
CN1098068C true CN1098068C (zh) | 2003-01-08 |
Family
ID=23189144
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN95195094A Expired - Lifetime CN1098068C (zh) | 1994-09-16 | 1995-07-26 | 装有用于诊断和治疗的多相组合物的容器 |
Country Status (14)
Country | Link |
---|---|
US (1) | US5773024A (zh) |
EP (2) | EP0788348B1 (zh) |
JP (1) | JP4004063B2 (zh) |
CN (1) | CN1098068C (zh) |
AT (2) | ATE445390T1 (zh) |
AU (1) | AU708341B2 (zh) |
BR (1) | BR9509011B1 (zh) |
CA (1) | CA2200061C (zh) |
DE (2) | DE69533261T2 (zh) |
DK (2) | DK1588699T3 (zh) |
ES (2) | ES2225844T3 (zh) |
MX (1) | MX9701969A (zh) |
PT (2) | PT1588699E (zh) |
WO (1) | WO1996008234A1 (zh) |
Families Citing this family (75)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6088613A (en) * | 1989-12-22 | 2000-07-11 | Imarx Pharmaceutical Corp. | Method of magnetic resonance focused surgical and therapeutic ultrasound |
US5656211A (en) * | 1989-12-22 | 1997-08-12 | Imarx Pharmaceutical Corp. | Apparatus and method for making gas-filled vesicles of optimal size |
US5776429A (en) * | 1989-12-22 | 1998-07-07 | Imarx Pharmaceutical Corp. | Method of preparing gas-filled microspheres using a lyophilized lipids |
US5798091A (en) | 1993-07-30 | 1998-08-25 | Alliance Pharmaceutical Corp. | Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement |
US7083572B2 (en) * | 1993-11-30 | 2006-08-01 | Bristol-Myers Squibb Medical Imaging, Inc. | Therapeutic delivery systems |
US5545396A (en) | 1994-04-08 | 1996-08-13 | The Research Foundation Of State University Of New York | Magnetic resonance imaging using hyperpolarized noble gases |
US6743779B1 (en) * | 1994-11-29 | 2004-06-01 | Imarx Pharmaceutical Corp. | Methods for delivering compounds into a cell |
US6426058B1 (en) * | 1996-03-29 | 2002-07-30 | The Regents Of The University Of California | Enhancement of NMR and MRI in the presence of hyperpolarized noble gases |
AU736301B2 (en) * | 1996-05-01 | 2001-07-26 | Imarx Therapeutics, Inc. | Methods for delivering compounds into a cell |
EP0918546B1 (en) * | 1996-08-02 | 2008-10-15 | GE Healthcare AS | Improvements in or relating to contrast agents |
GB9617811D0 (en) * | 1996-08-27 | 1996-10-09 | Nycomed Imaging As | Improvements in or relating to contrast agents |
DE69738406T2 (de) | 1996-10-21 | 2008-12-04 | Ge Healthcare As | Verbesserungen in oder an Kontrastmitteln |
US6537246B1 (en) * | 1997-06-18 | 2003-03-25 | Imarx Therapeutics, Inc. | Oxygen delivery agents and uses for the same |
GB9708240D0 (en) | 1997-04-23 | 1997-06-11 | Nycomed Imaging As | Improvements in or relating to contrast agents |
US6416740B1 (en) | 1997-05-13 | 2002-07-09 | Bristol-Myers Squibb Medical Imaging, Inc. | Acoustically active drug delivery systems |
GB9717589D0 (en) * | 1997-08-19 | 1997-10-22 | Nycomed Imaging As | Improvements in or relating to contrast agents |
US20010003580A1 (en) * | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
DE69925461T2 (de) | 1998-02-09 | 2006-04-27 | Bracco International B.V. | Zielgerichtete abgabe von biologische-aktive medien |
US6523356B2 (en) | 1998-09-30 | 2003-02-25 | Medi-Physics, Inc. | Meted hyperpolarized noble gas dispensing methods and associated devices |
US6286319B1 (en) * | 1998-09-30 | 2001-09-11 | Medi-Physics, Inc. | Meted hyperpolarized noble gas dispensing methods and associated devices |
US6302848B1 (en) * | 1999-07-01 | 2001-10-16 | Sonotech, Inc. | In vivo biocompatible acoustic coupling media |
US6284222B1 (en) | 1998-11-03 | 2001-09-04 | Medi--Physics, Inc. | Hyperpolarized helium-3 microbubble gas entrapment methods |
US6572840B1 (en) | 1999-07-28 | 2003-06-03 | Bristol-Myers Squibb Pharma Company | Stable microbubbles comprised of a perfluoropropane encapsulated lipid moiety for use as an ultrasound contrast agent |
JP2003526437A (ja) * | 2000-03-13 | 2003-09-09 | メディ−フィジックス・インコーポレイテッド | ガス状過分極129Xeの直接注射を使用する診断処置並びに関連するシステムおよび生成物 |
US7061237B2 (en) * | 2000-07-13 | 2006-06-13 | The Regents Of The University Of California | Remote NMR/MRI detection of laser polarized gases |
US6652833B2 (en) * | 2000-07-13 | 2003-11-25 | The Regents Of The University Of California | Functionalized active-nucleus complex sensor |
US20030165431A1 (en) * | 2000-07-13 | 2003-09-04 | The Regents Of The University Of California | Method for detecting macromolecular conformational change and binding information |
US6793626B2 (en) | 2001-01-17 | 2004-09-21 | Fuji Photo Film Co., Ltd. | Ultrasonic scatterer, ultrasonic imaging method and ultrasonic imaging apparatus |
US7138104B2 (en) * | 2001-08-08 | 2006-11-21 | Bristol-Myers Squibb Company | Simultaneous imaging of cardiac perfusion and a vitronectin receptor targeted imaging agent |
US6838074B2 (en) | 2001-08-08 | 2005-01-04 | Bristol-Myers Squibb Company | Simultaneous imaging of cardiac perfusion and a vitronectin receptor targeted imaging agent |
EA006832B1 (ru) | 2002-02-06 | 2006-04-28 | Те Риджентс Оф Те Юниверсити Оф Калифорния | Ядерный магнитный резонанс, измеряемый с помощью сверхпроводящего квантового интерференционного датчика, и формирование изображения с помощью магнитного резонанса при сверхслабых полях |
US7700074B2 (en) * | 2002-02-07 | 2010-04-20 | Pettegrew Jay W | Method and system for diagnosis of neuropsychiatric disorders including chronic alcoholism |
US7407778B2 (en) | 2002-02-07 | 2008-08-05 | Pettegrew Jay W | Compounds, compositions and methods for treating neuropsychiatric disorders |
EP2272946B9 (en) | 2002-02-25 | 2015-06-24 | Vaxiion Therapeutics, LLC | Minicell compositions and methods |
US7211240B2 (en) * | 2002-03-01 | 2007-05-01 | Bracco International B.V. | Multivalent constructs for therapeutic and diagnostic applications |
US7261876B2 (en) | 2002-03-01 | 2007-08-28 | Bracco International Bv | Multivalent constructs for therapeutic and diagnostic applications |
WO2004065621A1 (en) | 2002-03-01 | 2004-08-05 | Dyax Corp. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
US8623822B2 (en) * | 2002-03-01 | 2014-01-07 | Bracco Suisse Sa | KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy |
US20050250700A1 (en) * | 2002-03-01 | 2005-11-10 | Sato Aaron K | KDR and VEGF/KDR binding peptides |
US7794693B2 (en) * | 2002-03-01 | 2010-09-14 | Bracco International B.V. | Targeting vector-phospholipid conjugates |
US7666979B2 (en) * | 2002-03-01 | 2010-02-23 | Bracco International B.V. | Methods for preparing multivalent constructs for therapeutic and diagnostic applications and methods of preparing the same |
US7985402B2 (en) * | 2002-03-01 | 2011-07-26 | Bracco Suisse Sa | Targeting vector-phospholipid conjugates |
WO2004078778A2 (en) | 2003-03-03 | 2004-09-16 | Dyax Corp. | PEPTIDES THAT SPECIFICALLY BIND HGF RECEPTOR (cMet) AND USES THEREOF |
CN1795198B (zh) * | 2003-05-29 | 2011-08-17 | 杰伊·W·佩特格尤 | 对神经精神疾病进行医学成像所用的甘油磷酸胆碱及其衍生物 |
US20060257842A1 (en) * | 2003-05-29 | 2006-11-16 | Pettegrew Jay W | Cryopreservation media and molecules |
ES2235642B2 (es) * | 2003-12-18 | 2006-03-01 | Gat Formulation Gmbh | Proceso de multi-microencapsulacion continuo para la mejora de la estabilidad y almacenamiento de ingredientes biologicamente activos. |
AU2004320514B8 (en) * | 2004-06-04 | 2009-08-27 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
FR2876907B1 (fr) * | 2004-10-27 | 2007-02-23 | Serge Bernstein | Solutions aqueuses pour la reduction de tissus graisseux |
US7276905B2 (en) * | 2005-07-11 | 2007-10-02 | General Electric Company | Method and system of tracking an intracorporeal device with MR imaging |
US8257338B2 (en) * | 2006-10-27 | 2012-09-04 | Artenga, Inc. | Medical microbubble generation |
WO2007070827A2 (en) * | 2005-12-15 | 2007-06-21 | Bristol-Myers Squibb Pharma Company | Contrast agents for myocardium perfusion imaging |
WO2007071052A1 (en) * | 2005-12-21 | 2007-06-28 | Uti Limited Partnership | Treatment of respiratory diseases |
JP2007126467A (ja) * | 2006-12-15 | 2007-05-24 | Bracco Research Sa | 超音波造影媒体、この媒体を含む造影剤及び方法 |
AU2009210741A1 (en) * | 2008-02-07 | 2009-08-13 | Amgen Inc. | Stabilized protein compositions |
GB0811856D0 (en) | 2008-06-27 | 2008-07-30 | Ucl Business Plc | Magnetic microbubbles, methods of preparing them and their uses |
CA2834968C (en) * | 2011-01-05 | 2018-01-09 | Livon Laboratories | Methods of making liposomes, liposome compositions made by the methods, and methods of using the same |
JP2011140527A (ja) * | 2011-04-20 | 2011-07-21 | Acusphere Inc | 超音波造影剤の投薬処方物 |
US8798716B1 (en) * | 2011-11-03 | 2014-08-05 | Solstice Corporation | Fiducial markers and related methods |
WO2013164269A1 (en) * | 2012-04-30 | 2013-11-07 | Ge Healthcare As | Method for filling a container with a foamable composition |
CN104147640A (zh) * | 2013-05-16 | 2014-11-19 | 吴学森 | 右旋聚乳酸微纳米颗粒用作美容整形填充物及其制备方法 |
CN103815907B (zh) * | 2014-03-04 | 2016-04-06 | 合肥工业大学 | 用于人体呼吸系统检测成像的成像气体及其储气装置 |
US10456483B2 (en) * | 2014-12-03 | 2019-10-29 | University Of Cincinnati | Gas-encapsulated acoustically responsive stabilized microbubbles and methods for treating cardiovascular disease |
KR102618877B1 (ko) | 2014-12-31 | 2023-12-28 | 랜티우스 메디컬 이메징, 인크. | 지질-캡슐화된 기체 마이크로스피어 조성물 및 관련 방법 |
US20180085477A1 (en) | 2015-04-08 | 2018-03-29 | Sonocore, Inc. | Method for manufacturing bubbles |
JP6947636B2 (ja) * | 2015-04-20 | 2021-10-13 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニアThe Regents Of The University Of California | カプセル化された気体または部分真空のct造影材料 |
KR101620090B1 (ko) * | 2015-04-20 | 2016-05-12 | 주식회사 티젤바이오 | 약물전달 키트, 약물전달체 제조용 기구, 및 약물전달체 제조방법 |
MX2017014130A (es) | 2015-05-04 | 2018-07-06 | Versantis AG | Metodo para preparar vesiculas con gradiente de ph de transmembrana. |
JP5927325B1 (ja) * | 2015-05-25 | 2016-06-01 | SonoCore株式会社 | バブルの製造方法 |
WO2017040553A1 (en) | 2015-09-03 | 2017-03-09 | Schlumberger Technology Corporation | On the fly mixing of acids and diversion fluids with water-soluble retarding agents |
US11091689B2 (en) | 2015-09-03 | 2021-08-17 | Schlumberger Technology Corporation | Emulsions containing water-soluble acid retarding agents and methods of making and using |
WO2017040562A1 (en) | 2015-09-03 | 2017-03-09 | Schlumberger Technology Corporation | Diversion acid containing a water-soluble retarding agent and methods of making and using |
JP6539215B2 (ja) * | 2016-01-25 | 2019-07-03 | SonoCore株式会社 | バブルの製造方法 |
IL262647B2 (en) | 2016-05-04 | 2023-03-01 | Lantheus Medical Imaging Inc | Methods and devices for preparing sharpness factors for ultrasound |
US9789210B1 (en) | 2016-07-06 | 2017-10-17 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
WO2018053601A1 (en) * | 2016-09-23 | 2018-03-29 | The University Of Queensland | Method for preparing a lipid bubble |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4544545A (en) * | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
WO1990004384A1 (en) * | 1988-10-20 | 1990-05-03 | Royal Free Hospital School Of Medicine | Liposomes |
US5219538A (en) * | 1987-03-13 | 1993-06-15 | Micro-Pak, Inc. | Gas and oxygen carrying lipid vesicles |
Family Cites Families (121)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3532500A (en) * | 1967-07-25 | 1970-10-06 | Eastman Kodak Co | Light sensitive vesicular composition comprising an azido-s-triazine compound |
US3873564A (en) * | 1971-03-03 | 1975-03-25 | Synvar Ass | 2-Imidazolinyl-3-oxide-1-oxypropionic acid |
CH588887A5 (zh) * | 1974-07-19 | 1977-06-15 | Battelle Memorial Institute | |
US4162282A (en) * | 1976-04-22 | 1979-07-24 | Coulter Electronics, Inc. | Method for producing uniform particles |
GB1599881A (en) * | 1977-02-02 | 1981-10-07 | Millington A R | Preparation for diagnostic radiology |
CH621479A5 (zh) * | 1977-08-05 | 1981-02-13 | Battelle Memorial Institute | |
CH624011A5 (zh) * | 1977-08-05 | 1981-07-15 | Battelle Memorial Institute | |
US4192859A (en) * | 1978-09-29 | 1980-03-11 | E. R. Squibb & Sons, Inc. | Contrast media containing liposomes as carriers |
US4310506A (en) * | 1979-02-22 | 1982-01-12 | California Institute Of Technology | Means of preparation and applications of liposomes containing high concentrations of entrapped ionic species |
US4276885A (en) * | 1979-05-04 | 1981-07-07 | Rasor Associates, Inc | Ultrasonic image enhancement |
US4310505A (en) * | 1979-11-08 | 1982-01-12 | California Institute Of Technology | Lipid vesicles bearing carbohydrate surfaces as lymphatic directed vehicles for therapeutic and diagnostic substances |
US4344929A (en) * | 1980-04-25 | 1982-08-17 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
US4315514A (en) * | 1980-05-08 | 1982-02-16 | William Drewes | Method and apparatus for selective cell destruction |
US4331654A (en) * | 1980-06-13 | 1982-05-25 | Eli Lilly And Company | Magnetically-localizable, biodegradable lipid microspheres |
US4442843A (en) * | 1980-11-17 | 1984-04-17 | Schering, Ag | Microbubble precursors and methods for their production and use |
US4657756A (en) * | 1980-11-17 | 1987-04-14 | Schering Aktiengesellschaft | Microbubble precursors and apparatus for their production and use |
US4681119A (en) * | 1980-11-17 | 1987-07-21 | Schering Aktiengesellschaft | Method of production and use of microbubble precursors |
US4533254A (en) * | 1981-04-17 | 1985-08-06 | Biotechnology Development Corporation | Apparatus for forming emulsions |
EP0068961A3 (fr) * | 1981-06-26 | 1983-02-02 | Thomson-Csf | Dispositif d'échauffement localisé de tissus biologiques |
US4426330A (en) * | 1981-07-20 | 1984-01-17 | Lipid Specialties, Inc. | Synthetic phospholipid compounds |
US4534899A (en) * | 1981-07-20 | 1985-08-13 | Lipid Specialties, Inc. | Synthetic phospholipid compounds |
US4569836A (en) * | 1981-08-27 | 1986-02-11 | Gordon Robert T | Cancer treatment by intracellular hyperthermia |
DE3141641A1 (de) * | 1981-10-16 | 1983-04-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Ultraschall-kontrastmittel und dessen herstellung |
FR2534487B1 (fr) | 1982-10-15 | 1988-06-10 | Dior Christian Parfums | Procede d'homogeneisation de dispersions de phases lamellaires lipidiques hydratees, et suspensions obtenues par ce procede |
EP0111386B1 (en) * | 1982-10-26 | 1987-11-19 | University Of Aberdeen | Ultrasound hyperthermia unit |
US4603044A (en) * | 1983-01-06 | 1986-07-29 | Technology Unlimited, Inc. | Hepatocyte Directed Vesicle delivery system |
US4731239A (en) * | 1983-01-10 | 1988-03-15 | Gordon Robert T | Method for enhancing NMR imaging; and diagnostic use |
US4572203A (en) * | 1983-01-27 | 1986-02-25 | Feinstein Steven B | Contact agents for ultrasonic imaging |
US4718433A (en) * | 1983-01-27 | 1988-01-12 | Feinstein Steven B | Contrast agents for ultrasonic imaging |
US4775522A (en) * | 1983-03-04 | 1988-10-04 | Children's Hospital Research Foundation, A Division Of Children's Hospital Medical Center | NMR compositions for indirectly detecting a dissolved gas in an animal |
US4981692A (en) * | 1983-03-24 | 1991-01-01 | The Liposome Company, Inc. | Therapeutic treatment by intramammary infusion |
US5141738A (en) * | 1983-04-15 | 1992-08-25 | Schering Aktiengesellschaft | Ultrasonic contrast medium comprising gas bubbles and solid lipophilic surfactant-containing microparticles and use thereof |
US4900540A (en) * | 1983-06-20 | 1990-02-13 | Trustees Of The University Of Massachusetts | Lipisomes containing gas for ultrasound detection |
US4615879A (en) * | 1983-11-14 | 1986-10-07 | Vanderbilt University | Particulate NMR contrast agents for gastrointestinal application |
FR2563725B1 (fr) * | 1984-05-03 | 1988-07-15 | Dory Jacques | Appareil d'examen et de localisation de tumeurs par ultrasons muni d'un dispositif de traitement localise par hyperthermie |
GB8407557D0 (en) * | 1984-03-23 | 1984-05-02 | Hayward J A | Polymeric lipsomes |
US4728575A (en) * | 1984-04-27 | 1988-03-01 | Vestar, Inc. | Contrast agents for NMR imaging |
US5008050A (en) * | 1984-06-20 | 1991-04-16 | The Liposome Company, Inc. | Extrusion technique for producing unilamellar vesicles |
US4620546A (en) * | 1984-06-30 | 1986-11-04 | Kabushiki Kaisha Toshiba | Ultrasound hyperthermia apparatus |
US4921706A (en) * | 1984-11-20 | 1990-05-01 | Massachusetts Institute Of Technology | Unilamellar lipid vesicles and method for their formation |
US4830858A (en) * | 1985-02-11 | 1989-05-16 | E. R. Squibb & Sons, Inc. | Spray-drying method for preparing liposomes and products produced thereby |
US4689986A (en) * | 1985-03-13 | 1987-09-01 | The University Of Michigan | Variable frequency gas-bubble-manipulating apparatus and method |
US5186922A (en) * | 1985-03-15 | 1993-02-16 | See/Shell Biotechnology, Inc. | Use of biodegradable microspheres labeled with imaging energy constrast materials |
WO1986006959A1 (en) * | 1985-05-22 | 1986-12-04 | Liposome Technology, Inc. | Liposome inhalation method and system |
DE3677112D1 (de) | 1985-08-12 | 1991-02-28 | Battelle Memorial Institute | Poroese filtrierungsglaskugeln und methode zu deren herstellung. |
US4684479A (en) * | 1985-08-14 | 1987-08-04 | Arrigo Joseph S D | Surfactant mixtures, stable gas-in-liquid emulsions, and methods for the production of such emulsions from said mixtures |
US4938947A (en) * | 1985-11-01 | 1990-07-03 | Centre National De La Recherche Scientifique (Cnrs) | Aerosol composition for in vivo imaging |
US4927623A (en) * | 1986-01-14 | 1990-05-22 | Alliance Pharmaceutical Corp. | Dissolution of gas in a fluorocarbon liquid |
US4987154A (en) * | 1986-01-14 | 1991-01-22 | Alliance Pharmaceutical Corp. | Biocompatible, stable and concentrated fluorocarbon emulsions for contrast enhancement and oxygen transport in internal animal use |
US4865836A (en) * | 1986-01-14 | 1989-09-12 | Fluoromed Pharmaceutical, Inc. | Brominated perfluorocarbon emulsions for internal animal use for contrast enhancement and oxygen transport |
DE3785054T2 (de) | 1986-01-24 | 1993-07-08 | Childrens Hosp Medical Center | Stabile emulsionen von stark fluorierten, organischen verbindungen. |
US4737323A (en) * | 1986-02-13 | 1988-04-12 | Liposome Technology, Inc. | Liposome extrusion method |
JPH0751496B2 (ja) * | 1986-04-02 | 1995-06-05 | 武田薬品工業株式会社 | リポソ−ムの製造法 |
DE3614657A1 (de) | 1986-04-30 | 1987-11-05 | Dornier Medizintechnik | Pharmaka enthaltende lipidvesikel, verfahren zu ihrer herstellung und einbringung in den koerper eines lebewesens und freisetzung der in den lipidvesikeln enthaltende pharmaka |
IL79559A0 (en) | 1986-07-29 | 1986-10-31 | Univ Ramot | Contrast agents for nmr medical imaging |
US4728578A (en) * | 1986-08-13 | 1988-03-01 | The Lubrizol Corporation | Compositions containing basic metal salts and/or non-Newtonian colloidal disperse systems and vinyl aromatic containing polymers |
US4776991A (en) * | 1986-08-29 | 1988-10-11 | The United States Of America As Represented By The Secretary Of The Navy | Scaled-up production of liposome-encapsulated hemoglobin |
US4781871A (en) * | 1986-09-18 | 1988-11-01 | Liposome Technology, Inc. | High-concentration liposome processing method |
ZW11287A1 (en) * | 1986-11-04 | 1989-01-25 | Aeci Ltd | Process for the production of an explosive |
DE3637926C1 (de) * | 1986-11-05 | 1987-11-26 | Schering Ag | Ultraschall-Manometrieverfahren in einer Fluessigkeit mittels Mikroblaeschen |
US5049388A (en) * | 1986-11-06 | 1991-09-17 | Research Development Foundation | Small particle aerosol liposome and liposome-drug combinations for medical use |
US4863717A (en) * | 1986-11-10 | 1989-09-05 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The University Of Oregon | Methods for circumventing the problem of free radial reduction associated with the use of stable nitroxide free radicals as contrast agents for magnetic reasonance imaging |
DK175531B1 (da) | 1986-12-15 | 2004-11-22 | Nexstar Pharmaceuticals Inc | Leveringsvehikel med amphiphil-associeret aktiv bestanddel |
US5000960A (en) * | 1987-03-13 | 1991-03-19 | Micro-Pak, Inc. | Protein coupling to lipid vesicles |
IE61591B1 (en) | 1987-12-29 | 1994-11-16 | Molecular Biosystems Inc | Concentrated stabilized microbubble-type ultrasonic imaging agent and method of production |
US4844882A (en) * | 1987-12-29 | 1989-07-04 | Molecular Biosystems, Inc. | Concentrated stabilized microbubble-type ultrasonic imaging agent |
US5425366A (en) | 1988-02-05 | 1995-06-20 | Schering Aktiengesellschaft | Ultrasonic contrast agents for color Doppler imaging |
US4898734A (en) * | 1988-02-29 | 1990-02-06 | Massachusetts Institute Of Technology | Polymer composite for controlled release or membrane formation |
DE3812816A1 (de) | 1988-04-16 | 1989-11-02 | Lawaczeck Ruediger Dipl Phys P | Verfahren zur solubilisierung von liposomen und/oder biologischer membranen sowie deren verwendung |
US5171755A (en) * | 1988-04-29 | 1992-12-15 | Hemagen/Pfc | Emulsions of highly fluorinated organic compounds |
US4893624A (en) * | 1988-06-21 | 1990-01-16 | Massachusetts Institute Of Technology | Diffuse focus ultrasound hyperthermia system |
US4996041A (en) * | 1988-08-19 | 1991-02-26 | Toshiyuki Arai | Method for introducing oxygen-17 into tissue for imaging in a magnetic resonance imaging system |
US5045304A (en) * | 1988-08-31 | 1991-09-03 | Wayne State University | Contras agent having an imaging agent coupled to viable granulocytes for use in magnetic resonance imaging of abscess and a method of preparing and using same |
US5410516A (en) * | 1988-09-01 | 1995-04-25 | Schering Aktiengesellschaft | Ultrasonic processes and circuits for performing them |
US4957656A (en) * | 1988-09-14 | 1990-09-18 | Molecular Biosystems, Inc. | Continuous sonication method for preparing protein encapsulated microbubbles |
IL91664A (en) * | 1988-09-28 | 1993-05-13 | Yissum Res Dev Co | Ammonium transmembrane gradient system for efficient loading of liposomes with amphipathic drugs and their controlled release |
FR2637182B1 (fr) * | 1988-10-03 | 1992-11-06 | Lvmh Rech | Compositions a base de phases lamellaires lipidiques hydratees ou de liposomes contenant un ecdysteroide, de preference l'ecdysterone, ou l'un de ses derives; et compositions cosmetiques, pharmaceutiques, notamment dermatologiques, de sericulture ou phytosanitaires l'incorporant |
US5006343A (en) * | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
LU87449A1 (fr) * | 1989-02-09 | 1990-09-19 | Oreal | Procede de fabrication de mousses utilisables dans les domaines cosmetique et pharmaceutique et mousses obtenues par ce procede |
US4925993A (en) * | 1989-06-14 | 1990-05-15 | Dixie Chemical Company | Process for preparing chlorofluorocarbons via an in situ generated activated aluminum trichloride catalyst and products resulting therefrom |
US5114703A (en) * | 1989-05-30 | 1992-05-19 | Alliance Pharmaceutical Corp. | Percutaneous lymphography using particulate fluorocarbon emulsions |
ATE92931T1 (de) * | 1989-06-22 | 1993-08-15 | Atta | Fluor- und phosphorhaltige amphiphilische molekuele mit oberflaechenaktiven eigenschaften. |
US5194266A (en) * | 1989-08-08 | 1993-03-16 | Liposome Technology, Inc. | Amphotericin B/cholesterol sulfate composition and method |
US5013556A (en) * | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5305757A (en) * | 1989-12-22 | 1994-04-26 | Unger Evan C | Gas filled liposomes and their use as ultrasonic contrast agents |
US5088499A (en) * | 1989-12-22 | 1992-02-18 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
US5352435A (en) * | 1989-12-22 | 1994-10-04 | Unger Evan C | Ionophore containing liposomes for ultrasound imaging |
US5334381A (en) * | 1989-12-22 | 1994-08-02 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
US5230882A (en) * | 1989-12-22 | 1993-07-27 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
US5209720A (en) * | 1989-12-22 | 1993-05-11 | Unger Evan C | Methods for providing localized therapeutic heat to biological tissues and fluids using gas filled liposomes |
US5585112A (en) * | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
US5149319A (en) * | 1990-09-11 | 1992-09-22 | Unger Evan C | Methods for providing localized therapeutic heat to biological tissues and fluids |
US5228446A (en) * | 1989-12-22 | 1993-07-20 | Unger Evan C | Gas filled liposomes and their use as ultrasonic contrast agents |
US5542935A (en) * | 1989-12-22 | 1996-08-06 | Imarx Pharmaceutical Corp. | Therapeutic delivery systems related applications |
US5123414A (en) * | 1989-12-22 | 1992-06-23 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
US5445813A (en) | 1992-11-02 | 1995-08-29 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
IN172208B (zh) * | 1990-04-02 | 1993-05-01 | Sint Sa | |
US5190982A (en) * | 1990-04-26 | 1993-03-02 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
US5205287A (en) * | 1990-04-26 | 1993-04-27 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
US5137928A (en) * | 1990-04-26 | 1992-08-11 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
US5315997A (en) * | 1990-06-19 | 1994-05-31 | Molecular Biosystems, Inc. | Method of magnetic resonance imaging using diamagnetic contrast |
US5215680A (en) * | 1990-07-10 | 1993-06-01 | Cavitation-Control Technology, Inc. | Method for the production of medical-grade lipid-coated microbubbles, paramagnetic labeling of such microbubbles and therapeutic uses of microbubbles |
US5487390A (en) | 1990-10-05 | 1996-01-30 | Massachusetts Institute Of Technology | Gas-filled polymeric microbubbles for ultrasound imaging |
WO1992005806A1 (en) * | 1990-10-05 | 1992-04-16 | Sintetica S.A. | Method for the preparation of stable suspensions of hollow gas-filled microspheres suitable for ultrasonic echography |
GB9106686D0 (en) | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
GB9106673D0 (en) | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
US5496535A (en) | 1991-04-12 | 1996-03-05 | Alliance Pharmaceutical Corp. | Fluorocarbon contrast media for use with MRI and radiographic imaging |
US5147631A (en) * | 1991-04-30 | 1992-09-15 | Du Pont Merck Pharmaceutical Company | Porous inorganic ultrasound contrast agents |
US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
AU2789192A (en) * | 1991-10-04 | 1993-05-03 | Mallinckrodt Medical, Inc. | Gaseous ultrasound contrast agents |
US5196183A (en) * | 1991-12-04 | 1993-03-23 | Sterling Winthrop Inc. | Contrast agents for ultrasound imaging |
IL104084A (en) | 1992-01-24 | 1996-09-12 | Bracco Int Bv | Sustainable aqueous suspensions of pressure-resistant and gas-filled blisters, their preparation, and contrast agents containing them |
WO1993015722A1 (en) | 1992-02-07 | 1993-08-19 | Syntex (Usa) Inc. | Controlled delivery of pharmaceuticals from preformed porous microparticles |
US5362478A (en) | 1993-03-26 | 1994-11-08 | Vivorx Pharmaceuticals, Inc. | Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell |
DE4308601A1 (de) | 1993-03-18 | 1994-09-22 | Kolbus Gmbh & Co Kg | Förderer zum Überführen von Büchern, Blocks o. dgl. in eine gedrehte neue Lage |
US5716597A (en) | 1993-06-04 | 1998-02-10 | Molecular Biosystems, Inc. | Emulsions as contrast agents and method of use |
CA2166459C (en) | 1993-07-02 | 2000-03-28 | Karel J. Lambert | Methods for making encapsulated microspheres from heat denatured protein |
US5433204A (en) | 1993-11-16 | 1995-07-18 | Camilla Olson | Method of assessing placentation |
US5562893A (en) | 1994-08-02 | 1996-10-08 | Molecular Biosystems, Inc. | Gas-filled microspheres with fluorine-containing shells |
US5540909A (en) | 1994-09-28 | 1996-07-30 | Alliance Pharmaceutical Corp. | Harmonic ultrasound imaging with microbubbles |
US5560364A (en) | 1995-05-12 | 1996-10-01 | The Board Of Regents Of The University Of Nebraska | Suspended ultra-sound induced microbubble cavitation imaging |
-
1994
- 1994-09-16 US US08/307,305 patent/US5773024A/en not_active Expired - Lifetime
-
1995
- 1995-07-26 ES ES95927429T patent/ES2225844T3/es not_active Expired - Lifetime
- 1995-07-26 ES ES04076135T patent/ES2335206T3/es not_active Expired - Lifetime
- 1995-07-26 MX MX9701969A patent/MX9701969A/es unknown
- 1995-07-26 DE DE69533261T patent/DE69533261T2/de not_active Expired - Lifetime
- 1995-07-26 AT AT04076135T patent/ATE445390T1/de active
- 1995-07-26 JP JP51017496A patent/JP4004063B2/ja not_active Expired - Lifetime
- 1995-07-26 CA CA002200061A patent/CA2200061C/en not_active Expired - Lifetime
- 1995-07-26 PT PT04076135T patent/PT1588699E/pt unknown
- 1995-07-26 EP EP95927429A patent/EP0788348B1/en not_active Expired - Lifetime
- 1995-07-26 PT PT95927429T patent/PT788348E/pt unknown
- 1995-07-26 DK DK04076135.5T patent/DK1588699T3/da active
- 1995-07-26 WO PCT/US1995/009392 patent/WO1996008234A1/en active IP Right Grant
- 1995-07-26 AU AU31465/95A patent/AU708341B2/en not_active Expired
- 1995-07-26 CN CN95195094A patent/CN1098068C/zh not_active Expired - Lifetime
- 1995-07-26 BR BRPI9509011-8A patent/BR9509011B1/pt not_active IP Right Cessation
- 1995-07-26 DE DE69536012T patent/DE69536012D1/de not_active Expired - Lifetime
- 1995-07-26 DK DK95927429T patent/DK0788348T3/da active
- 1995-07-26 AT AT95927429T patent/ATE270878T1/de not_active IP Right Cessation
- 1995-07-26 EP EP04076135A patent/EP1588699B1/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4544545A (en) * | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
US5219538A (en) * | 1987-03-13 | 1993-06-15 | Micro-Pak, Inc. | Gas and oxygen carrying lipid vesicles |
WO1990004384A1 (en) * | 1988-10-20 | 1990-05-03 | Royal Free Hospital School Of Medicine | Liposomes |
Also Published As
Publication number | Publication date |
---|---|
MX9701969A (es) | 1998-02-28 |
EP0788348A4 (en) | 1998-04-01 |
ES2225844T3 (es) | 2005-03-16 |
JPH10505900A (ja) | 1998-06-09 |
PT788348E (pt) | 2004-09-30 |
ATE445390T1 (de) | 2009-10-15 |
EP0788348B1 (en) | 2004-07-14 |
ATE270878T1 (de) | 2004-07-15 |
JP4004063B2 (ja) | 2007-11-07 |
BR9509011B1 (pt) | 2009-01-13 |
DE69533261T2 (de) | 2005-08-04 |
US5773024A (en) | 1998-06-30 |
PT1588699E (pt) | 2010-01-19 |
DE69533261D1 (de) | 2004-08-19 |
DK0788348T3 (da) | 2004-11-29 |
CA2200061A1 (en) | 1996-03-21 |
CA2200061C (en) | 2007-04-10 |
ES2335206T3 (es) | 2010-03-23 |
AU3146595A (en) | 1996-03-29 |
BR9509011A (pt) | 1997-09-30 |
EP1588699A2 (en) | 2005-10-26 |
EP1588699A3 (en) | 2006-01-18 |
EP1588699B1 (en) | 2009-10-14 |
CN1158082A (zh) | 1997-08-27 |
DK1588699T3 (da) | 2010-03-01 |
EP0788348A1 (en) | 1997-08-13 |
WO1996008234A1 (en) | 1996-03-21 |
AU708341B2 (en) | 1999-08-05 |
DE69536012D1 (de) | 2009-11-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1098068C (zh) | 装有用于诊断和治疗的多相组合物的容器 | |
CN1221214C (zh) | 制备最佳尺寸的充气泡囊的装置和方法 | |
US6551576B1 (en) | Container with multi-phase composition for use in diagnostic and therapeutic applications | |
US6146657A (en) | Gas-filled lipid spheres for use in diagnostic and therapeutic applications | |
CN1238699A (zh) | 造影剂或与造影剂有关的改进 | |
CN1149259A (zh) | 作为计算机化x射线断层照相术对比剂的稳定均匀的悬浮液 | |
CZ191695A3 (en) | Biologically compatible contrast agent, process of its preparation and representation method by ultrasound | |
CN1180310A (zh) | 新的含类脂和稳定剂的组合物 | |
JP2023089124A (ja) | 脂質カプセル化ガスマイクロスフェア組成物および関連方法 | |
CN1180304A (zh) | 磁共振聚焦的用于外科手术和治疗的超声术的方法 | |
MXPA97009717A (en) | Apparatus and method for making vessels filled with opt size gas |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term |
Expiration termination date: 20150726 Granted publication date: 20030108 |
|
EXPY | Termination of patent right or utility model |