SK113795A3 - Contrast agent, preparation method thereof and its application - Google Patents
Contrast agent, preparation method thereof and its application Download PDFInfo
- Publication number
- SK113795A3 SK113795A3 SK1137-95A SK113795A SK113795A3 SK 113795 A3 SK113795 A3 SK 113795A3 SK 113795 A SK113795 A SK 113795A SK 113795 A3 SK113795 A3 SK 113795A3
- Authority
- SK
- Slovakia
- Prior art keywords
- contrast agent
- gas
- agent according
- liposome
- forming
- Prior art date
Links
- 239000002872 contrast media Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title description 2
- 239000000463 material Substances 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 238000009472 formulation Methods 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 11
- 238000002595 magnetic resonance imaging Methods 0.000 claims abstract description 9
- 238000002059 diagnostic imaging Methods 0.000 claims abstract description 5
- 238000012285 ultrasound imaging Methods 0.000 claims abstract description 4
- 239000007789 gas Substances 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000002502 liposome Substances 0.000 claims description 10
- 238000000576 coating method Methods 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- -1 alkaline earth metal carbonates Chemical class 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000011248 coating agent Substances 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 239000007900 aqueous suspension Substances 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- 239000008350 hydrogenated phosphatidyl choline Substances 0.000 claims description 3
- 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 claims description 3
- 150000008105 phosphatidylcholines Chemical class 0.000 claims description 3
- 150000008106 phosphatidylserines Chemical class 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000560 biocompatible material Substances 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- BLRXYTIIKIPJQL-UHFFFAOYSA-N dicarbide(1-) Chemical class [C-]#C BLRXYTIIKIPJQL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 150000001247 metal acetylides Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 125000000962 organic group Chemical group 0.000 claims description 2
- 229920000515 polycarbonate Polymers 0.000 claims description 2
- 239000004417 polycarbonate Substances 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 239000003566 sealing material Substances 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical group 0.000 claims 1
- 239000012736 aqueous medium Substances 0.000 claims 1
- 125000005587 carbonate group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 11
- 239000007788 liquid Substances 0.000 abstract description 6
- 239000008215 water for injection Substances 0.000 abstract description 6
- 210000004369 blood Anatomy 0.000 abstract description 2
- 239000008280 blood Substances 0.000 abstract description 2
- 210000001124 body fluid Anatomy 0.000 abstract description 2
- 239000010839 body fluid Substances 0.000 abstract 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000011859 microparticle Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000003384 imaging method Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000001569 carbon dioxide Substances 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000000386 microscopy Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 2
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229940039231 contrast media Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000013081 microcrystal Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- BDBMLMBYCXNVMC-UHFFFAOYSA-O 4-[(2e)-2-[(2e,4e,6z)-7-[1,1-dimethyl-3-(4-sulfobutyl)benzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS(O)(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C BDBMLMBYCXNVMC-UHFFFAOYSA-O 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010056388 Albunex Proteins 0.000 description 1
- 239000005997 Calcium carbide Substances 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 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 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004716 alpha keto acids Chemical class 0.000 description 1
- AFVLVVWMAFSXCK-VMPITWQZSA-N alpha-cyano-4-hydroxycinnamic acid Chemical group OC(=O)C(\C#N)=C\C1=CC=C(O)C=C1 AFVLVVWMAFSXCK-VMPITWQZSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- JINBYESILADKFW-UHFFFAOYSA-N aminomalonic acid Chemical class OC(=O)C(N)C(O)=O JINBYESILADKFW-UHFFFAOYSA-N 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004718 beta keto acids Chemical class 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 239000002961 echo contrast media Substances 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- DANUORFCFTYTSZ-UHFFFAOYSA-N epinigericin Natural products O1C2(C(CC(C)(O2)C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)C)C(C)C(OC)CC1CC1CCC(C)C(C(C)C(O)=O)O1 DANUORFCFTYTSZ-UHFFFAOYSA-N 0.000 description 1
- 230000002169 extracardiac Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 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
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960004657 indocyanine green Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000002555 ionophore Substances 0.000 description 1
- 230000000236 ionophoric effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- SFDZETWZUCDYMD-UHFFFAOYSA-N monosodium acetylide Chemical compound [Na+].[C-]#C SFDZETWZUCDYMD-UHFFFAOYSA-N 0.000 description 1
- DANUORFCFTYTSZ-BIBFWWMMSA-N nigericin Chemical compound C([C@@H]1C[C@H]([C@H]([C@]2([C@@H](C[C@](C)(O2)C2O[C@@](C)(CC2)C2[C@H](CC(O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C)O1)C)OC)[C@H]1CC[C@H](C)C([C@@H](C)C(O)=O)O1 DANUORFCFTYTSZ-BIBFWWMMSA-N 0.000 description 1
- 150000005677 organic carbonates Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- MMCOUVMKNAHQOY-UHFFFAOYSA-L oxido carbonate Chemical compound [O-]OC([O-])=O MMCOUVMKNAHQOY-UHFFFAOYSA-L 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000012418 sodium perborate tetrahydrate Substances 0.000 description 1
- IBDSNZLUHYKHQP-UHFFFAOYSA-N sodium;3-oxidodioxaborirane;tetrahydrate Chemical compound O.O.O.O.[Na+].[O-]B1OO1 IBDSNZLUHYKHQP-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- CLZWAWBPWVRRGI-UHFFFAOYSA-N tert-butyl 2-[2-[2-[2-[bis[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]amino]-5-bromophenoxy]ethoxy]-4-methyl-n-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]anilino]acetate Chemical compound CC1=CC=C(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(OCCOC=2C(=CC=C(Br)C=2)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)=C1 CLZWAWBPWVRRGI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
- 235000014101 wine Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Physics & Mathematics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
Abstract
Description
Kontrastné činidlo, spôsob jeho prípravy a použitieContrast agent, process for its preparation and use
Oblasť technikyTechnical field
Vynález sa týka nových kontrastných činidiel, konkrétnejšie nových mikročasticových kontrastných činidiel na použitie v diagnostickom zobrazovaní.The invention relates to novel contrast agents, more particularly to novel microparticle contrast agents for use in diagnostic imaging.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Zobrazovanie ultrazvukom sa zakladá na prenikaní ultrazvukových vín, napríklad vo frekvenčnej oblasti 1 až 10 MHz, do ľudského alebo zvieracieho subjektu cez menič, pričom ultrazvukové vlny interagujú s rozhraniami telesných tkanív a tekutín. Kontrast ultrazvukového obrazu pochádza z diferenciálneho odrazu/absorpcie zvukových vín na takýchto rozhraniach; výsledky možno zlepšiť Dopplerovou technikou vrátane použitia farebného Dopplera na vyhodnotenie prúdenia krvi.Ultrasonic imaging is based on the penetration of ultrasonic wines, for example in the frequency range of 1 to 10 MHz, into a human or animal subject via a transducer, the ultrasonic waves interacting with body tissue and fluid interfaces. The ultrasound image contrast comes from the differential reflection / absorption of the sound waves at such interfaces; results can be improved by the Doppler technique, including the use of colored Doppler to assess blood flow.
Už dávno sa zistilo, že môže byť výhodné zväčšiť rozdiel v akustických vlastnostiach rôznych tkanív/tekutín použitím kontrastných činidiel a od použitia indocyanínovej zelenej v roku 1968 ako prvého kontrastného činidla sa vyskúšali mnohé ďalšie potenciálne činidlá. Tieto zahrnujú emulzie, tuhé častice, vo vode rozpustné zlúčeniny, voľné plynové bubliny a rôzne typy systémov, obsahujúcich uzavretý plyn. Všeobecne sa uznáva, že kontrastné činidlá s nízkou hustotou, ktoré sú ľahko stlačiteľné, sú zvlášť účinné z hľadiska spätného akustického rozptylu, ktorý vytvárajú; teda plyn obsahujúce a plyn tvoriace systémy prejavujú tendenciu vykazovať výrazne vyššiu účinnosť než iné typy kontrastných činidiel.It has long been found that it may be advantageous to increase the difference in the acoustic properties of different tissues / fluids using contrast agents and many other potential agents have been tried since the use of indocyanine green in 1968 as the first contrast agent. These include emulsions, solid particles, water-soluble compounds, free gas bubbles, and various types of closed gas containing systems. It is generally accepted that low-density contrast agents that are easily compressible are particularly effective in terms of the back-scattering they produce; thus, gas-containing and gas-generating systems tend to exhibit significantly higher efficacy than other types of contrast agents.
V súčasnosti sú komerčne dostupné, alebo v pokročilom klinickom vývoji, tri ultrazvukové kontrastné činidlá, ktorými sú Echovist na báze plyn obsahujúcich mikrokryštálov n galaktózy; Levovist , obsahujúci plyn obsahujúce mikrokryšp tály galaktózy, pokryté mastnou kyselinou; a Albunex , ktorý obsahuje plynové bubliny, uzavreté čiastočne denaturovaným ľudským sérom albumín.Currently, three ultrasonic contrast agents are commercially available, or in advanced clinical development, which are Echovist based on gas-containing microcrystals of n galactose; Levovist, comprising a gas containing galactose microcrystals coated with a fatty acid; and Albunex, which contains gas bubbles, closed with partially denatured human serum albumin.
Je známe, že plyn obsahujúce kontrastné médiá sú účinné tiež pri zobrazovaní magnetickou rezonanciou (MR), napríklad ako susceptibilitné kontrastné činidlá, ktoré budú spôsobovať zmenšovanie intenzity MR signálu. Kyslík obsahujúce kontrastné médiá tiež reprezentujú potenciálne užitočné paramagnetické MR kontrastné činidlá.It is known that gas containing contrast media is also effective in magnetic resonance imaging (MR) imaging, for example, as susceptible contrast agents that will reduce the intensity of the MR signal. Oxygen-containing contrast media also represent potentially useful paramagnetic MR contrast agents.
Naviac, v oblasti zobrazovania rontgenovým žiarením sa zistilo, že plyny, ako je oxid uhličitý, možno použiť ako negatívne orálne kontrastné činidlá.In addition, it has been found in the field of X-ray imaging that gases such as carbon dioxide can be used as negative oral contrast agents.
Všeobecnou nevýhodou väčšiny existujúcich plyn obsahujúcich a plyn tvoriacich kontrastných činidiel je ich relatívny nedostatok stability in vivo. To je špeciálny problém v oblastiach, ako je echokardiografia, kde existuje potreba zlepšených kontrastných činidiel, schopných vytvárať mikrobubliny dostatočne malé na to, aby prešli cez pľúcnu kapilárnu sieť (t.j. typicky s veľkosťou menšou než asi 10 μιη, s výhodou menej než asi 7 gm) a tak umožnili zviditeľniť ľavú stranu srdca, a ktoré sú s výhodou dostatočne stabilné na to, aby vydržali niekoľko prechodov v obehu.A general disadvantage of most existing gas-containing and gas-generating contrast agents is their relative lack of stability in vivo. This is a particular problem in areas such as echocardiography where there is a need for improved contrast agents capable of forming microbubbles small enough to pass through the pulmonary capillary network (ie typically having a size of less than about 10 μιη, preferably less than about 7 gm). ) and thus allow the left side of the heart to be visible and which are preferably sufficiently stable to withstand several transitions in circulation.
Je tiež žiadúce, aby kontrastné činidlá vykazovali dobrú stabilitu pri dlhodobom skladovaní, napríklad viac než jeden rok, s výhodou 2 až 3 roky alebo viac.It is also desirable that the contrast agents exhibit good long-term storage stability, for example more than one year, preferably 2 to 3 years or more.
Podstata vynálezuSUMMARY OF THE INVENTION
Tento vynález sa zakladá na našom zistení, že mikročasticové materiály, ktoré sú schopné chemicky vytvárať plyn po formulovaní s vhodnou nosnou kvapalinou, napríklad vodou pre injekciu, a/alebo po podaní subjektu, napríklad ako výsledok vystavenia pôsobeniu krvi alebo inej telesnej tekutiny, môžu byť užitočné ako kontrastné činidlá v diagnostickom zobrazovaní .The present invention is based on our discovery that microparticulate materials that are capable of chemically producing gas upon formulation with a suitable carrier liquid, e.g., water for injection, and / or after administration to a subject, e.g., as a result of exposure to blood or other bodily fluid. useful as contrast agents in diagnostic imaging.
Takéto činidlá možno považovať za odlišné od existujúcich mikročasticových kontrastných činidiel, ako sú vyššie D p uvedené Echovist a Levovist , kde tvorba mikrobublín je v podstate len fyzikálnym procesom, týkajúcim sa plynu, nachádzajúceho sa na alebo v mikročasticiach, napríklad ako inklúzie v dutinách ich kryštálových štruktúr a/alebo priľnutý k ich povrchom. Je zrejmé, že použitie kontrastných činidiel podľa tohto vynálezu môže viesť k tvorbe mikrobublín z takto fyzikálne adsorbovaného plynu, ako aj z chemicky tvoreného plynu, a že toto môže zlepšiť celkovú intenzitu kontrastného efektu.Such agents may be considered different from existing microparticulate contrast agents such as the above D p mentioned by Echovist and Levovist, where microbubble formation is essentially a physical process related to the gas present on or in the microparticles, for example as inclusion in the cavities of their crystal. structures and / or adhered to their surfaces. It will be appreciated that the use of the contrast agents of the present invention may result in the formation of microbubbles from both physically adsorbed gas and chemically generated gas, and that this may improve the overall intensity of the contrast effect.
Kontrastné činidlá, ktoré obsahujú látky, chemicky tvoriace plyn, uzavreté v lipozómoch, už boli opísané napríklad vo VO-A-9109629. Keďže stabilné lipozómy bezpodmienečne vyžadujú hydrofilné jadro, uzavreté látky budú typicky prítomné vo forme roztoku vo vode alebo v inom relatívne hydrofilnom rozpúšťadle; kontrastný účinok takýchto kontrastných činidiel bude obmedzený' maximálnym obsahom plyn tvoriacej látky, ktorý sa môže zaviesť do roztoku v lipozómových jadrách. Naviac, takéto lipozómové produkty budú mať tendenciu vykazovať nižšiu dlhodobú stabilitu pri skladovaní než suché mikročasticové materiály podľa tohto vynálezu v dôsledku faktorov, ako sú spájanie bublín a presakovanie.Liposome-encapsulated contrast agents containing chemically gas-forming agents have already been described, for example, in WO-A-9109629. Since stable liposomes absolutely require a hydrophilic core, the sealed substances will typically be present as a solution in water or other relatively hydrophilic solvent; the contrast effect of such contrast agents will be limited by the maximum content of gas-forming agent that can be introduced into the solution in the liposome cores. In addition, such liposome products will tend to exhibit lower long-term storage stability than the dry microparticle materials of the present invention due to factors such as bubble bonding and leakage.
Podľa jedného aspektu tohto vynálezu sa poskytuje kontrastné činidlo, ktoré obsahuje tuhú mikročasticovú látku, schopnú chemickej tvorby plynu pri formulovaní kontrastného činidla do nosnej kvapaliny a/alebo pri podaní formulovaného kontrastného činidla ľudskému alebo zvieraciemu subjektu.According to one aspect of the present invention, there is provided a contrast agent comprising a solid microparticulate material capable of chemically generating gas when formulating the contrast agent into a carrier liquid and / or administering the formulated contrast agent to a human or animal subject.
Takéto kontrastné činidlá možno použiť u mnohých diagnostických zobrazovacích metód, vrátane ultrazvukového, MR a rôntgenového zobrazovania, pričom ich použitie v diagnostickom ultrazvukovom zobrazovaní a MR zobrazovaní, napríklad ako susceptibilitných kontrastných činidiel, predstavuje výhodné znaky tohto vynálezu.Such contrast agents can be used in a variety of diagnostic imaging methods, including ultrasound, MR and X-ray imaging, and their use in diagnostic ultrasound imaging and MR imaging, for example, as susceptible contrast agents, constitutes advantageous features of the present invention.
Plyn tvoriacou látkou môže byť napríklad jednotlivá zlúčenina, ktorá reaguje chemicky (pričom tento výraz sa tu používa tak, že zahrnuje enzymatickú reakciu), aby vytvárala plyn po podaní subjektu, napríklad ako dôsledok rozkladu, vyvolaného termicky alebo zmenou pH, alebo ako výsledok enzymatického rozkladu. Teda napríklad netoxické anorganické a organické karbonáty, napríklad karbonáty a bikarbonáty alkalických kovov a kovov alkalických zemín, arginínkarbonát a zlúčeniny vzorca RO.CO.OM, kde R je organická skupina a M reprezentuje fyziologicky prijateľný katión, budú tvoriť oxid uhličitý za podmienok pH, ktoré prevažujú v krvnom riečišti, tak ako zlúčeniny, ako sú aminomalonáty.For example, the gas generating agent may be a single compound that reacts chemically (as used herein to include an enzymatic reaction) to produce a gas upon administration to a subject, for example, as a result of thermal or pH-induced degradation or as a result of enzymatic degradation. . Thus, for example, non-toxic inorganic and organic carbonates, such as alkali and alkaline earth metal carbonates and bicarbonates, arginine carbonate, and compounds of formula RO.CO.OM, where R is an organic group and M represents a physiologically acceptable cation, will form carbon dioxide under pH conditions they predominate in the bloodstream, as do compounds such as aminomalonates.
Karboxylové kyseliny, ako sú kyselina malónová, a- kyanokyseliny, α-nitrokyseliny, a-arylkyseliny, a-ketokyseliny, a,a,a-trihalogénkyseliny, β-ketokyseliny a p,gama-nenasýtené kyseliny relatívne ľahko dekarboxylujú, čo sa môže odohrávať spontánne in vivo s vývojom oxidu uhličitého.Carboxylic acids such as malonic acid, α-cyano acids, α-nitro acids, α-aryl acids, α-keto acids, α, α, α-trihalo acids, β-keto acids and β, gamma-unsaturated acids decarboxylate relatively easily, which can occur spontaneously in vivo with the development of carbon dioxide.
Metyléndiestery (napríklad pripravené s použitím spôsobov, ako sú opísané vo VO-A-9317718 a VO-A-9318070, obsah ktorých je sem zahrnutý odkazom) sa štiepia bežnými esterázami.’čo vedie k vývoju oxidu uhličitého. Takéto deriváty diesterov, napríklad zlúčenín, ako sú dextrány, môžu preto poskytovať užitočné kontrastné činidlá podľa tohto vynálezu.Methylene diesters (for example, prepared using methods such as described in WO-A-9317718 and WO-A-9318070, the contents of which are incorporated herein by reference) are cleaved by conventional esterases. This leads to the development of carbon dioxide. Such diester derivatives, for example compounds such as dextrans, may therefore provide useful contrast agents of the invention.
Peroxid vodíka, ktorý môže byť prítomný v antioxidantom stabilizovanej tuhej formulácii alebo časticovej matrici, ako je komplex polyvinylpyrolidón-peroxid vodíka (pozri napríklad VO-A-9107184), alebo v prekurzorovej forme, napríklad ako je tetrahydrát peroxoboritanu sodného (pozri napríklad EP-A-0253772) alebo peroxid močoviny (pozri napríklad VO-A-9011248), sa enzymaticky rozkladá za vývoja kyslíka.Hydrogen peroxide, which may be present in an antioxidant-stabilized solid formulation or particulate matrix such as polyvinylpyrrolidone hydrogen peroxide complex (see for example WO-A-9107184) or in a precursor form such as sodium perborate tetrahydrate (see for example EP-A -0253772) or urea peroxide (see, for example, WO-A-9011248), enzymatically decomposes to produce oxygen.
Je zrejmé, že vyššie uvedené kontrastné činidlá podľa tohto vynálezu zostávajú po formulovaní stabilnými, ’napríklad ako roztoky v injektovateľných médiách, ako je voda pre injekciu, pričom tvorba plynu sa nezačne pred uskutočnením podania. Takéto formulácie tvoria ďalší znak tohto vynálezu.It will be appreciated that the aforementioned contrast agents of the present invention remain stable after formulation, for example as solutions in injectable media such as water for injection, and gas formation does not begin prior to administration. Such formulations constitute a further feature of the invention.
Ďalšia skupina plyn tvoriacich látok zahrnuje zlúčeniny, ktoré reagujú s vodou za tvorby plynu; kontrastné činidlá s takýmito zlúčeninami začnú vytvárať mikrobubliny ihneď po formulovaní do napríklad vody pre injekciu. Reprezentatívne zlúčeniny tohto typu zahrnujú hydridy, ako sú tetrahydroboritan sodný alebo hydrid vápnika; acetylénidy, ako je acetylid sodný; karbidy, ako je karbid vápnika; N-karboxyanhydridy (pozri napríklad J.Am.Chem.Soc. 112.Another group of gas generators includes compounds that react with water to form a gas; contrast agents with such compounds begin to form microbubbles immediately upon formulation in, for example, water for injection. Representative compounds of this type include hydrides such as sodium borohydride or calcium hydride; acetylenides such as sodium acetylide; carbides such as calcium carbide; N-carboxyanhydrides (see, for example, J. Am. Chem. Soc. 112.
17414 až 7416, 1990), ktoré reakciou poskytujú oxid uhličitý a aminokyselinu; a polykarbonáty (pozri napríklad Pope a spol. v Org.Synth.Coll. Vol. VI (1988), str. 418), napríklad zlúčeniny vzorca (CH3)3C.O.(CO2)n.C(CH3)3 kde n je najmenej 2, ktoré reagujú s vodou za tvorby oxidu uhličitého.17414-7416 (1990) which give carbon dioxide and an amino acid by reaction; and polycarbonates (see, for example, Pope et al. in Org. Synth.Coll. Vol. VI (1988), p. 418), for example, compounds of formula (CH 3 ) 3 CO (CO 2 ) n .C (CH 3 ) 3 wherein n is at least 2 which react with water to form carbon dioxide.
. Alternatívne môže plyn tvoriaca látka zahrnovať množstvo zlúčenín, ktoré možno skladovať oddelene alebo v kombinácii, a ktoré reagujú, keď sa, napríklad, formulujú do vody pre injekciu. Príklady zahrnujú tradičné šumivé systémy, typicky obsahujúce karbonát alebo bikarbonát (napríklad s netoxickými alkalickými kovmi alebo kovmi alkalických zemín) a organickú kyselinu, ako je kyselina vínna, jantárová alebo citrónová. Iné reprezentatívne kombinované formulácie zahrnujú peroxokarbonát/bikarbonát sodný/kyselinu citrónovú, j 5-nitrofurylakrylát/kyselina etyléndiamíntetraoctová/kyselina askorbová/kyselina vínna/disiričitan sodný/bikarbonát sodný, a polyfosfáty s dlhými reťazcami/bikarbonát sodný.. Alternatively, the gas-generating substance may comprise a plurality of compounds that can be stored separately or in combination and which react when, for example, formulated into water for injection. Examples include traditional effervescent systems, typically comprising carbonate or bicarbonate (for example, with non-toxic alkali or alkaline earth metals) and an organic acid such as tartaric, succinic or citric acid. Other representative combination formulations include peroxycarbonate / sodium bicarbonate / citric acid, 5-nitropuryl acrylate / ethylenediaminetetraacetic acid / ascorbic acid / tartaric acid / sodium metabisulphite / sodium bicarbonate, and long chain polyphosphates / sodium bicarbonate.
Mikročasticový materiál možno, ak je to potrebné, stabilizovať, napríklad potiahnutím alebo uzavretím do vhodného biokompatibilného materiálu, ktorý možno vybrať napríklad , tak, aby bol rozpustný a/alebo biodegradovateľný. Reprezentatívne materiály teda zahrnujú polyetylénglykoly, pluroniká, albumín, želatínu, škrob, kolagén, dextrány, polylaktid/polyglykolid, blokové kopolyméry a biodegradovatelné polyméry, ako sú opísané vo VO-A-9204392, VO-A-9317718 a VO-A-9318070. Potiahnutie/uzavretie môže zahrnovať ionofóry, ako je nigericín, na uľahčenie prenosu protónov cez ne v prípadoch, kde sa plyn tvoriaca látka aktivuje pH zmenou.The microparticulate material may, if necessary, be stabilized, for example by coating or encapsulating in a suitable biocompatible material, which may be selected, for example, to be soluble and / or biodegradable. Representative materials thus include polyethylene glycols, pluronic, albumin, gelatin, starch, collagen, dextrans, polylactide / polyglycolide, block copolymers and biodegradable polymers as described in WO-A-9204392, WO-A-9317718 and WO-A-93180. The coating / capping may include ionophores, such as nigericin, to facilitate transfer of protons therethrough in cases where the gas-generating substance is activated by pH change.
Mikročasticový materiál možno s výhodou stabilizovať v prolipozómovej forme, napríklad, ako opísali Payne a spol. v J.Pharm.Sci. 75., 325 až 329, 1986, Katare a spol.Preferably, the microparticle material can be stabilized in a proliposome form, for example, as described by Payne et al. in J.Pharm.Sci. 75, 325-329 (1986); Qatar et al.
v J.Microencapsulation 7, 455 až 462, 1990, a Ibid. 8, 1 ažin J. Microencapsulation 7, 455-462, 1990, and Ibid. 8, 1 to
7, 1991, obsah ktorých je sem zahrnutý odkazom. V zásade ta6 kéto produkty obsahujú mikročasticový materiál, potiahnutý lipozóm tvoriacim materiálom (napríklad fosfolipidom, ako je ' fosfatidylcholín, hydrogenovaný fosfatidylcholín alebo hydrogenovaný fosfatidylserín) v suchej forme. Produkty tohto typu typicky obsahujú suché, voľne tečúce prášky a vykazujú zvlášť dobrú dlhodobú stabilitu pri skladovaní. Tvorbu lipozómu bude normálne sprevádzať tvorba plynu, keď sa produkt formuluje do vodnej nosnej kvapaliny, ako je voda pre injekciu. Alternatívne môže byť poťahujúci materiál taký, že je v podstate nepriepustný, alebo je ináč inertný k nosnej kvapaline, ale sa modifikuje alebo aktivuje pri alebo bezprostredne pred podaním, napríklad, aby vykazoval zlepšenú priepustnosť, napríklad ako výsledok zmeny pH alebo enzýmovej aktivity, čo vedie na tvorbu lipozómu a tvorbu plynu in vivo po podaní. Vodné suspenzie a disperzie posledne uvedenej triedy prolipozómov môžu teda vykazovať dobrú stabilitu pri skladovaní a tvoria ďalší znak tohto vynálezu. Stabilitu takýchto vodných formulácií možno, ak je to žiadúce, zlepšiť í vhodným výberom podmienok, ako je pH, napríklad pufrovaním formulácie k slabej zásaditosti, aby sa zabezpečilo, že pred jej podaním nenastane v podstate žiadna tvorba plynu.7, 1991, the contents of which are incorporated herein by reference. Essentially, these products comprise microparticulate material coated with a liposome-forming material (for example, a phospholipid such as phosphatidylcholine, hydrogenated phosphatidylcholine or hydrogenated phosphatidylserine) in dry form. Products of this type typically contain dry, free-flowing powders and exhibit particularly good long-term storage stability. The formation of the liposome will normally be accompanied by the formation of gas when the product is formulated in an aqueous carrier liquid, such as water for injection. Alternatively, the coating material may be such that it is substantially impermeable, or otherwise inert to the carrier liquid, but is modified or activated at or immediately prior to administration, for example, to exhibit improved permeability, for example, as a result of pH change or enzyme activity resulting for liposome formation and gas generation in vivo after administration. Aqueous suspensions and dispersions of the latter class of proliposomes may therefore exhibit good storage stability and constitute a further feature of the present invention. The stability of such aqueous formulations may, if desired, be improved by appropriately selecting conditions such as pH, for example, by buffering the formulation to weak alkalinity to ensure that substantially no gas formation occurs prior to administration.
Je zrejmé, že lipozómy, vytvárané kontrastnými činidlami v prolipozómovej forme, môžu podporovať stabilizáciu mikrobublín, ktoré sa tvoria v dôsledku ich dlhého zotrvania , napríklad v cievnom systéme.It will be appreciated that the liposomes produced by the contrast agents in the proliposome form can promote the stabilization of microbubbles that are formed due to their long residence, for example in the vascular system.
Ak je to potrebné, mikročasticový materiál v kontrast. ných činidlách podľa tohto vynálezu môže obsahovať rozpustenú látku, slúžiacu na vytvorenie osmotického gradientu na zlepšenie difúzie kvapaliny cez povlak do materiálu.If necessary, the microparticulate material in contrast. The compositions of the present invention may include a solute to form an osmotic gradient to enhance liquid diffusion through the coating into the material.
Stabilitu mikrobublín možno vo všeobecnosti zlepšiť mikročasticami plyn tvoriacej látky, ktoré samotné pôsobia ako kondenzačné zárodky. Mikročastice môžu tiež mať pórovitú alebo špongiovú štruktúru, napríklad obsahujúcu plyn tvoriaci materiál v póroch alebo sieťach štruktúry, alebo s plynovými vakmi alebo dutinami, vytvorenými na povrchu častíc; flexibilita takýchto štruktúr zlepší ich echogenicitu v porovnaní s tuhšími, plyn obsahujúcimi systémami.Microbubble stability can generally be improved by gas-forming microparticles, which themselves act as condensation nuclei. The microparticles may also have a porous or sponge structure, for example, containing gas-forming material in the pores or meshes of the structure, or with gas bags or cavities formed on the surface of the particles; the flexibility of such structures will improve their echogenicity compared to more rigid, gas-containing systems.
Kontrastné činidlá podľa tohto vynálezu možno pripraviť ľubovoľnou vhodnou metódou, napríklad mikromletím plyn tvoI riacej látky. Pred alebo po takomto mikromletí možno aplikovať ľubovoľný poťahovací alebo uzatvárací materiál. Teda napríklad, s výhodou hydrofilnú, mikromletú, plyn tvoriacu látku možno dispergovať v prchavom lipofilnom rozpúšťadle, v ktorom sa požadovaný poťahovací materiál rozpustí pred, v priebehu alebo po dispergačnom kroku, po ktorom sa rozpúšťadlo odstráni, napríklad za zníženého tlaku, aby vznikol potiahnutý mikročasticový produkt podľa tohto vynálezu.The contrast agents of the present invention can be prepared by any suitable method, for example by micronising the gas generating agent. Any coating or sealing material may be applied before or after such micronizing. Thus, for example, preferably a hydrophilic, micronized, gas-forming substance can be dispersed in a volatile lipophilic solvent in which the desired coating material is dissolved before, during, or after the dispersion step after which the solvent is removed, for example under reduced pressure to form a coated microparticle. the product of the invention.
Vo všeobecnosti možno použiť bežné mikromlecie techniky, ako je drvenie alebo mletie; mletie v guľovom mlyne môže byť zvlášť vhodné.In general, conventional micronising techniques such as crushing or grinding may be used; milling in a ball mill may be particularly suitable.
Poťahovanie/uzatváranie možno taktiež dosiahnuť s použitím bežných metód, napríklad vo fluidizačnom lôžku, sprayovaním, lisovaním, máčaním, oddelením koacervačnej fázy, mnohoštrbinovou centrifugačnou technikou a technikou odparovania rozpúšťadla, aby vznikli povlaky vhodného zloženia, hrúbky a priepustnosti v jednej alebo viacerých vrstvách.Coating / sealing may also be achieved using conventional methods, for example, in a fluidized bed, spraying, pressing, dipping, coacervation phase separation, multi-slot centrifugation and solvent evaporation techniques to form coatings of suitable composition, thickness and permeability in one or more layers.
Kontrastné činidlá podľa tohto vynálezu možno podávať napríklad enterálne alebo parenterálne, hoci v konkrétnych prípadoch môže byť výhodné podanie priamo do telesných dutín, ako sú Fallopiove trubice. Vo všeobecnosti je však najpravdepodobnejšie intravaskulárne podanie, najčastejšie int, ravenóznou injekciou, aby sa zlepšilo zobrazenie ciev, vrátane srdcovej a mimosrdcovej perfúzie.For example, the contrast agents of the invention may be administered enterally or parenterally, although in particular cases administration directly into body cavities such as Fallopian tubes may be advantageous. In general, however, intravascular administration, most often int, is most likely a ravenous injection to improve vascular imaging, including cardiac and extracardiac perfusion.
. Je zrejmé, že kontrastné činidlá na intravenózne podanie by mali vytvárať mikrobubliny dostatočne malé na to, aby prešli cez kapilárnu sieť pľúcneho systému. Činidlá by preto s výhodou mali byť také, aby vytvárali mikrobubliny s priemerom menším než 10 gm, s výhodou v rozsahu 0,2 až 8 gm, napríklad 0,3 až 7 gm; mikročastice môžu vhodne mať napríklad priemernú veľkosť 1 až 7 gm, napríklad 1 až 4 gm. Podstatne väčšie veľkosti mikročastíc a mikrobublín, napríklad do 500 gm, môžu byť užitočné v aplikáciách, ako je zobrazovanie gastrointestinálneho traktu.. Obviously, contrast agents for intravenous administration should produce microbubbles small enough to pass through the capillary network of the lung system. The agents should therefore preferably be such as to form microbubbles with a diameter of less than 10 gm, preferably in the range of 0.2 to 8 gm, for example 0.3 to 7 gm; the microparticles may conveniently have, for example, an average size of 1 to 7 gm, for example 1 to 4 gm. Substantially larger microparticle and microbubble sizes, for example up to 500 gm, may be useful in applications such as gastrointestinal imaging.
Nasledujúce neobmedzujúce príklady slúžia na ilustráciu vynálezu.The following non-limiting examples serve to illustrate the invention.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Fosfatidylcholín (2,5 g) sa pridal k suspenzii bezvodého bikarbonátu sodného (10 g) v chloroforme (30 ml) a nechal . sa rozpustiť. Rozpúšťadlo sa potom odtsránilo za zníženého tlaku pri 40 C, aby vznikol tuhý produkt.Phosphatidylcholine (2.5 g) was added to a suspension of anhydrous sodium bicarbonate (10 g) in chloroform (30 mL) and left. to dissolve. The solvent was then removed under reduced pressure at 40 ° C to give a solid product.
. Vzorka tohto produktu (100 mg) sa rozpustila vo vodnom roztoku glukózy (5 ml roztoku 50 mg/ml) a roztok sa okyslil na pH 2 pridaním kyseliny chlorovodíkovej a zahrial sa na 50 “C. Vytvorila sa zakalená suspenzia, v ktorej prítomné častice mali tendenciu vyplávať na povrch. Svetelná mikroskopia ukázala, že sa vytvorili lipozómy a že bubliny obsahovali plyn.. A sample of this product (100 mg) was dissolved in aqueous glucose solution (5 ml of a 50 mg / ml solution) and the solution was acidified to pH 2 by addition of hydrochloric acid and heated to 50 ° C. A cloudy suspension was formed in which the particles present tended to float to the surface. Light microscopy showed that liposomes had formed and that the bubbles contained gas.
Príklad 2Example 2
I Suspenzia jemnozrnného bezvodého karbonátu sodného (1,6 g) v chloroforme (20 ml) sa sonikovala niekoľko minút, aby sa rozrušili aglomeráty. Pridal sa hydrogenovaný fosfatidylcholín (280 mg) a rozpustil sa v suspenzii za miešania. Rozpúšťadlo sa potom odstránilo za zníženého tlaku pri 40 ’C, aby vznikol tuhý prášok.A suspension of fine-grained anhydrous sodium carbonate (1.6 g) in chloroform (20 ml) was sonicated for several minutes to disrupt the agglomerates. Hydrogenated phosphatidylcholine (280 mg) was added and dissolved in the suspension with stirring. The solvent was then removed under reduced pressure at 40 ° C to give a solid powder.
. Vzorka tohto produktu (100 mg) sa pridala k vodnému roztoku kyseliny askorbovej (2 ml roztoku 25 mg/ml), čo . viedlo k vytvoreniu zakalenej suspenzie, v ktorej prítomné častice mali tendenciu vyplávať na povrch. Svetelná mikroskopia ukázala, že sa vytvorili lipozómy a že bubliny obsahovali plyn.. A sample of this product (100 mg) was added to an aqueous solution of ascorbic acid (2 ml of a 25 mg / ml solution). resulted in the formation of a cloudy suspension in which the particles present tended to float to the surface. Light microscopy showed that liposomes had formed and that the bubbles contained gas.
Príklad 3Example 3
Suspenzia jemnozrnného bezvodého karbonátu sodného (1,6 g) v chloroforme (20 ml) sa sonikovala niekoľko minút, aby sa rozrušili aglomeráty. Pridal sa hydrogenovaný fosfatidylserín (280 mg), rozpustil sa v suspenzii za miešania a pridal sa glycerol (4 ml). Rozpúšťadlo sa potom odstránilo za zníženého tlaku pri 40 C, aby vznikol bezvodý koncentrát .A suspension of fine-grained anhydrous sodium carbonate (1.6 g) in chloroform (20 ml) was sonicated for several minutes to disrupt the agglomerates. Hydrogenated phosphatidylserine (280 mg) was added, dissolved in the suspension with stirring, and glycerol (4 mL) was added. The solvent was then removed under reduced pressure at 40 ° C to give an anhydrous concentrate.
Vzorka tohto produktu (200 mg) sa pridala k vodnému roztoku glukózy (4 ml roztoku 50 mg/ml), na čo sa protónmi serínovej časti fosfolipidu vyvolala tvorba plynu karbonátom sodným, čo viedlo k vytvoreniu zakalenej suspenzie, v ktorej prítomné častice mali tendenciu vyplávať na povrch. Svetelná mikroskopia ukázala, že sa vytvorili lipozómy a že bubliny obsahovali plyn.A sample of this product (200 mg) was added to an aqueous glucose solution (4 ml of a 50 mg / ml solution), causing the protons of the serine portion of the phospholipid to induce gas formation with sodium carbonate, resulting in a cloudy suspension in which particles present tended to float. to the surface. Light microscopy showed that liposomes had formed and that the bubbles contained gas.
Príklad 4Example 4
Akustický účinok formulovaných produktov z príkladovThe acoustic effect of the formulated products of the examples
I až 3 sa určil ich ďalším desaťnásobným zriedením Isotonom1-3 were determined by a further ten-fold dilution with Isoton
II (Coulter Electronics Limited, Luton, Anglicko), umiestnením zriedených vzoriek v kyvetách do vodného kúpela, udržovaného pri 37 C a meraním akustického spätného rozptylu s použitím 3,5 MHz jednoprvkového meniča technikou odrazu impulzu. Vo všetkých prípadoch sa pozoroval silný akustický spätný rozptyl zvnútra kyvety, pričom referenčné meranie s kyvetou, ktorá obsahovala len Isoton II, neukázalo žiadny spätný rozptyl.II (Coulter Electronics Limited, Luton, England), by placing diluted samples in cuvettes in a water bath maintained at 37 C and measuring acoustic backscatter using a 3.5 MHz single element transducer technique. In all cases, a strong acoustic backscatter was observed from the inside of the cuvette, and a reference measurement with a cuvette containing only Isoton II showed no backscatter.
Príklad 5Example 5
Jemnozrnný prášok karbonátu sodného a bikarbonátu sodného (1:1 hmotnostné, 1,36 g) sa dispergoval v hexáne (20 ml), ktorý obsahoval Aerosol OT (1,75 g). Pridal sa Tween 60 (1,0 g), rozpustený vo vode (50 ml), a výsledná zmes sa emulziíikovala s použitím homogenizátora Ystral, poskytnúc jemnú emulziu.The fine-grained powder of sodium carbonate and sodium bicarbonate (1: 1 by weight, 1.36 g) was dispersed in hexane (20 ml) containing Aerosol OT (1.75 g). Tween 60 (1.0 g) dissolved in water (50 mL) was added, and the resulting mixture was emulsified using a Ystral homogenizer to give a fine emulsion.
Vzorka tohto produktu (2 ml) sa vstrekla do fosfátového pufra (5 ml). Výsledná zmes vykazovala echogenický účinok in vitro. pričom signál bol stabilný 20 minút.A sample of this product (2 mL) was injected into phosphate buffer (5 mL). The resulting mixture showed an echogenic effect in vitro. the signal was stable for 20 minutes.
Claims (15)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB939305351A GB9305351D0 (en) | 1993-03-16 | 1993-03-16 | Improvements in or relating to contrast agents |
| PCT/GB1994/000522 WO1994021302A1 (en) | 1993-03-16 | 1994-03-16 | Improvements in or relating to contrast agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK113795A3 true SK113795A3 (en) | 1997-02-05 |
Family
ID=10732118
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK1137-95A SK113795A3 (en) | 1993-03-16 | 1994-03-16 | Contrast agent, preparation method thereof and its application |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0689462A1 (en) |
| JP (1) | JPH08507781A (en) |
| KR (1) | KR960700760A (en) |
| CN (1) | CN1121314A (en) |
| AU (1) | AU695529B2 (en) |
| BR (1) | BR9406199A (en) |
| CA (1) | CA2158359A1 (en) |
| CZ (1) | CZ237195A3 (en) |
| FI (1) | FI954326A (en) |
| GB (1) | GB9305351D0 (en) |
| HU (1) | HUT72984A (en) |
| NO (1) | NO953638D0 (en) |
| PL (1) | PL310657A1 (en) |
| SK (1) | SK113795A3 (en) |
| WO (1) | WO1994021302A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9106673D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
| US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
| US5333613A (en) * | 1993-03-23 | 1994-08-02 | Delineate | Microparticles as ultrasonic contrast media |
| US5897851A (en) * | 1995-06-07 | 1999-04-27 | Sonus Pharmaceuticals, Inc. | Nucleation and activation of a liquid-in-liquid emulsion for use in ultrasound imaging |
| GB9511488D0 (en) * | 1995-06-07 | 1995-08-02 | Nycomed Imaging As | Improvements in or relating to contrast agents |
| GB9622711D0 (en) | 1996-10-31 | 1997-01-08 | British Tech Group | Instrument having enhanced ultrasound visibility |
| US6278893B1 (en) * | 1998-01-05 | 2001-08-21 | Nycomed Imaging As | Method of magnetic resonance imaging of a sample with ex vivo polarization of an MR imaging agent |
| US20010003580A1 (en) | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
| US20070110674A1 (en) * | 2005-07-29 | 2007-05-17 | Yuhong Xu | Sono-active liposomes and lipid particles and use thereof as contrast agents and active-agent delivery systems |
| CN113289034A (en) | 2014-12-31 | 2021-08-24 | 蓝瑟斯医学影像公司 | Lipid-encapsulated gas microsphere compositions and related methods |
| IL262647B2 (en) | 2016-05-04 | 2023-03-01 | Lantheus Medical Imaging Inc | Methods and devices for preparation of ultrasound contrast agents |
| US9789210B1 (en) | 2016-07-06 | 2017-10-17 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
| GB201821049D0 (en) * | 2018-12-21 | 2019-02-06 | Ge Healthcare As | Ultrasound contrast agent and methods for use therof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4900540A (en) * | 1983-06-20 | 1990-02-13 | Trustees Of The University Of Massachusetts | Lipisomes containing gas for ultrasound detection |
| 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 |
| JPH0678247B2 (en) * | 1988-10-04 | 1994-10-05 | 大塚製薬株式会社 | Iron-containing preparation for NMR contrast |
| US5147631A (en) * | 1991-04-30 | 1992-09-15 | Du Pont Merck Pharmaceutical Company | Porous inorganic ultrasound contrast agents |
| JP3650393B2 (en) * | 1992-03-06 | 2005-05-18 | アメルシャム ヘルス アクスイェ セルスカプ | Improvements in or on contrast media |
-
1993
- 1993-03-16 GB GB939305351A patent/GB9305351D0/en active Pending
-
1994
- 1994-03-16 JP JP6520776A patent/JPH08507781A/en active Pending
- 1994-03-16 AU AU62153/94A patent/AU695529B2/en not_active Ceased
- 1994-03-16 CZ CZ952371A patent/CZ237195A3/en unknown
- 1994-03-16 CN CN94191800A patent/CN1121314A/en active Pending
- 1994-03-16 KR KR1019950703924A patent/KR960700760A/en not_active Application Discontinuation
- 1994-03-16 SK SK1137-95A patent/SK113795A3/en unknown
- 1994-03-16 CA CA002158359A patent/CA2158359A1/en not_active Abandoned
- 1994-03-16 BR BR9406199A patent/BR9406199A/en not_active Application Discontinuation
- 1994-03-16 HU HU9502693A patent/HUT72984A/en unknown
- 1994-03-16 PL PL94310657A patent/PL310657A1/en unknown
- 1994-03-16 WO PCT/GB1994/000522 patent/WO1994021302A1/en not_active Application Discontinuation
- 1994-03-16 EP EP94909227A patent/EP0689462A1/en not_active Withdrawn
-
1995
- 1995-09-14 FI FI954326A patent/FI954326A/en unknown
- 1995-09-15 NO NO953638A patent/NO953638D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB9305351D0 (en) | 1993-05-05 |
| AU6215394A (en) | 1994-10-11 |
| EP0689462A1 (en) | 1996-01-03 |
| FI954326A0 (en) | 1995-09-14 |
| CN1121314A (en) | 1996-04-24 |
| NO953638L (en) | 1995-09-15 |
| HUT72984A (en) | 1996-06-28 |
| BR9406199A (en) | 1995-12-12 |
| JPH08507781A (en) | 1996-08-20 |
| PL310657A1 (en) | 1995-12-27 |
| FI954326A (en) | 1995-10-11 |
| KR960700760A (en) | 1996-02-24 |
| WO1994021302A1 (en) | 1994-09-29 |
| HU9502693D0 (en) | 1995-11-28 |
| NO953638D0 (en) | 1995-09-15 |
| AU695529B2 (en) | 1998-08-13 |
| CZ237195A3 (en) | 1996-05-15 |
| CA2158359A1 (en) | 1994-09-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU630030B2 (en) | Stable microbubbles suspensions injectable into living organisms | |
| JP3136016B2 (en) | Long-lasting suspension of pressure-resistant gas-filled microbubbles and its preparation | |
| TW480176B (en) | Polymer-lipid microencapsulated gases for use as imaging agents | |
| RU2204415C2 (en) | Combined preparation for using as contrasting agent and method of image preparing | |
| AU689086B2 (en) | Improvements in or relating to contrast agents | |
| EP0907380B1 (en) | Pressure resistant protein microspheres as ultrasonic imaging agents | |
| AU695529B2 (en) | Improvements in or relating to contrast agents | |
| EP0689461B1 (en) | Improvements in or relating to contrast agents | |
| JPH11500435A (en) | Use of a methylenemalonic diester derivative for producing gas-containing microparticles for ultrasonic diagnostics, and a drug containing the particles | |
| JP3819845B2 (en) | Improved method for measuring local physical parameters in fluid filled cavities | |
| CZ287115B6 (en) | Agent for ultrasonic diagnostics, ultrasonic contrast medium, set for preparing such contrast medium and process for preparing said agent | |
| CN101015701A (en) | In vivo reaction type micro air bubble ultrasonic contrast medium and its preparing process | |
| US20010019710A1 (en) | Contrast agents | |
| US20030064030A1 (en) | Ultrasound contrast agents and methods of making and using them |