EP0966305A1 - Agents de contraste contenant deux types de microbulles remplies de gaz - Google Patents
Agents de contraste contenant deux types de microbulles remplies de gazInfo
- Publication number
- EP0966305A1 EP0966305A1 EP98900940A EP98900940A EP0966305A1 EP 0966305 A1 EP0966305 A1 EP 0966305A1 EP 98900940 A EP98900940 A EP 98900940A EP 98900940 A EP98900940 A EP 98900940A EP 0966305 A1 EP0966305 A1 EP 0966305A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gas
- preparation
- types
- microparticle
- phospholipid
- 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.)
- Ceased
Links
- 239000002872 contrast media Substances 0.000 title claims description 30
- 239000011859 microparticle Substances 0.000 claims abstract description 49
- 239000002961 echo contrast media Substances 0.000 claims abstract description 4
- 239000007789 gas Substances 0.000 claims description 64
- 238000002360 preparation method Methods 0.000 claims description 34
- 150000003904 phospholipids Chemical class 0.000 claims description 19
- 238000002604 ultrasonography Methods 0.000 claims description 10
- 238000003384 imaging method Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 150000002430 hydrocarbons Chemical class 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- 230000003019 stabilising effect Effects 0.000 claims description 5
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000909 sulfur hexafluoride Drugs 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229920002988 biodegradable polymer Polymers 0.000 claims description 4
- 239000004621 biodegradable polymer Substances 0.000 claims description 4
- 150000008106 phosphatidylserines Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000002321 glycerophosphoglycerophosphoglycerols Chemical class 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 150000008103 phosphatidic acids Chemical class 0.000 claims description 3
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 3
- 229940067626 phosphatidylinositols Drugs 0.000 claims description 3
- ABQLAMJAQZFPJI-UHFFFAOYSA-N 3-heptyloxolan-2-one Chemical compound CCCCCCCC1CCOC1=O ABQLAMJAQZFPJI-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 150000008105 phosphatidylcholines Chemical class 0.000 claims description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 2
- 229940067605 phosphatidylethanolamines Drugs 0.000 claims description 2
- 150000004756 silanes Chemical class 0.000 claims description 2
- QTJXVIKNLHZIKL-UHFFFAOYSA-N sulfur difluoride Chemical class FSF QTJXVIKNLHZIKL-UHFFFAOYSA-N 0.000 claims description 2
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 claims 1
- 239000003570 air Substances 0.000 claims 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229910052756 noble gas Inorganic materials 0.000 claims 1
- 150000002835 noble gases Chemical class 0.000 claims 1
- 230000006378 damage Effects 0.000 abstract description 3
- 230000003993 interaction Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 239000006185 dispersion Substances 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- -1 pulullan Polymers 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000004108 freeze drying Methods 0.000 description 7
- KAVGMUDTWQVPDF-UHFFFAOYSA-N perflubutane Chemical class FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F KAVGMUDTWQVPDF-UHFFFAOYSA-N 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000004945 emulsification Methods 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 239000012736 aqueous medium Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 229920002307 Dextran Polymers 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- 102000008100 Human Serum Albumin Human genes 0.000 description 3
- 108091006905 Human Serum Albumin Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000008365 aqueous carrier Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000001924 fatty-acyl group Chemical group 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 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
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 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
- 229930195725 Mannitol Natural products 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical compound CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 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 2
- 230000000959 cryoprotective effect Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- NJCBUSHGCBERSK-UHFFFAOYSA-N perfluoropentane Chemical class FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F NJCBUSHGCBERSK-UHFFFAOYSA-N 0.000 description 2
- 229960004065 perflutren Drugs 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 238000012285 ultrasound imaging Methods 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
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 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
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- COQIQRBKEGPRSG-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoro-2-(trifluoromethyl)propane Chemical compound FC(F)(F)C(F)(C(F)(F)F)C(F)(F)F COQIQRBKEGPRSG-UHFFFAOYSA-N 0.000 description 1
- FNVLGCVAWPSVSK-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,5,5,6,6,7,7-tetradecafluorocycloheptane Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F FNVLGCVAWPSVSK-UHFFFAOYSA-N 0.000 description 1
- RKIMETXDACNTIE-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,5,5,6,6-dodecafluorocyclohexane Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F RKIMETXDACNTIE-UHFFFAOYSA-N 0.000 description 1
- QIROQPWSJUXOJC-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,5,5,6-undecafluoro-6-(trifluoromethyl)cyclohexane Chemical compound FC(F)(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F QIROQPWSJUXOJC-UHFFFAOYSA-N 0.000 description 1
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- CIWUYWQUYMZILR-UHFFFAOYSA-N 1,1,2,2,3,3,4,4-octafluoro-5,5-bis(trifluoromethyl)cyclopentane Chemical class FC(F)(F)C1(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C1(F)F CIWUYWQUYMZILR-UHFFFAOYSA-N 0.000 description 1
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- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
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- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 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
- 239000008227 sterile water for injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—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
- 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
Definitions
- This invention relates to ultrasound imaging, more particularly to novel contrast agent compositions and preparations comprising at least two types of gas- containing microparticles and to their preparation and use .
- ultrasound imaging comprises a potentially valuable diagnostic tool, for example in studies of the vascular system, particularly in cardiography, and of tissue microvasculature .
- contrast agents has been proposed to enhance the acoustic images so obtained, including suspensions of solid particles, emulsified liquid droplets, gas microbubbles and encapsulated gases or liquids.
- gas-containing and gas-generating systems has attracted particular interest, since the low density and ease of compressibility of gas present or generated in such systems ensure particularly efficient backscatter of ultrasound.
- porous gas-containing microparticles or as encapsulated gas microbubbles for example using encapsulating materials such as proteins, polymers or film-forming surfactants such as phospholipids .
- encapsulating materials such as proteins, polymers or film-forming surfactants such as phospholipids .
- thick encapsulating shells reduce the compressibility and thus the echogenicity of the microbubbles.
- certain biocompatible fluorocarbons may be used in the form of free gas microbubbles by virtue of their persistence relative to air in aqueous media such as blood.
- Contrast agents comprising encapsulated or otherwise stabilised dispersions of substantially water-insoluble fluorinated gases have also been proposed - see, for example, the disclosure of O-A-9501187 regarding protein microspheres containing water-insoluble gases such as perfluoropropane and the description of BR1 , a phospholipid-stabilised dispersion of sulphur hexafluoride- filled microbubbles, in Investigative Radiology 30 ( 8 ) , pp. 451-457.
- contrast agents tend to exhibit a higher echogenic response and lower attenuation than contrast agents having thicker and/or more rigid encapsulating shells, they do in consequence suffer the disadvantage that they have relatively low resistance to high acoustic pressure, for example such as may be encountered in the near field in close proximity to the ultrasound transducer. Imaging at diagnostically useful ultrasound intensities may therefore lead to substantial destruction of the contrast agent in the near field. It has been proposed to overcome this problem by imaging at low acoustic field strengths or by using intermittent ultrasound pulses, for example triggered by every tenth, twentieth or thirtieth cardiac cycle. However, this may prevent continuous imaging with good opacification in the near field and/or give rise to unacceptable signal to noise ratios in the far field remote from the transducer.
- the present invention is based, inter alia, on the finding that such disadvantages may be mitigated or overcome by use of contrast agents comprising two or more types of gas-containing microparticles which differ in their resistance to ultrasound energy, i.e. in their susceptibility to ultrasonic pressure.
- contrast agents comprising two or more types of gas-containing microparticles which differ in their resistance to ultrasound energy, i.e. in their susceptibility to ultrasonic pressure.
- microparticle types having relatively low susceptibility to ultrasonic pressure will provide a response to high acoustic energy in the near field where microparticle types with relatively high susceptibility will tend to be inactivated through destruction.
- the more highly susceptible microparticle types will, however, be effective in the lower acoustic energy environment of the far field, where lower susceptibility microparticle types will tend to exhibit little interaction.
- a combined preparation for simultaneous, separate or sequential use as an ultrasound contrast agent comprising at least two different types of gas-containing microparticles, said microparticle types differing in their susceptibility to ultrasonic pressure.
- a method of generating enhanced images of a human or non-human animal subject which comprises the steps of administering a contrast agent preparation as defined above to said subject and generating an ultrasound image of at least a part of said subject.
- the differing susceptibility to ultrasonic pressure of the microparticle types may result from physical and/or chemical differences.
- microparticle types which differ only in size, for example having a bimodal size distribution, in order to achieve the desired difference in susceptibility to ultrasonic pressure.
- different encapsulating or other stabilising systems will be employed, for example comprising a first microparticle type which has relatively soft encapsulating shells and therefore has relatively high susceptibility to ultrasonic pressure and a second microparticle type which has relatively hard encapsulating or otherwise stabilising material, e.g. in shell or matrix form, and therefore has relatively low susceptibility to ultrasonic pressure.
- the different microparticle types may be selected from any appropriate gas -containing microparticulate ultrasound contrast agents.
- Representative examples of such contrast agents include microbubbles of gas stabilised (e.g. at least partially encapsulated) by a coalescence-resistant surface membrane (for example gelatin, e.g. as described in WO-A-8002365) , a filmogenic protein (for example an albumin such as human serum albumin, e.g.
- WO-A-4718433 US-A- 4774958, US-A-4844882 , EP-A-0359246 , WO-A- 9112823 , WO-A- 9205806, WO-A-9217213 , WO-A-9406477 or WO-A-9501187)
- a polymer material for example a synthetic biodegradable polymer as described in EP-A-0398935 , an elastic interfacial synthetic polymer membrane as described in EP-A-0458745 , a microparticulate biodegradable polyaldehyde as described in EP-A-0441468 , a microparticulate N-dicarboxylic acid derivative of a polyamino acid - polycyclic imide as described in EP-A- 0458079, or a biodegradable polymer as described in WO- A-9317718 or WO-A-9607434 ) , a non-polymeric and non- polymer
- gas-containing microparticulate contrast agents include gas-containing solid systems, for example microparticles (especially aggregates of microparticles) having gas contained therewithin or otherwise associated therewith (for example being adsorbed on the surface thereof and/or contained within voids, cavities or pores therein, e.g. as described in EP-A-0122624, EP-A-0123235 , EP-A- 0365467 , WO-A- 9221382 , WO-A-9300930, WO-A-9313802 , WO-A-9313808 or WO-A- 9313809) .
- gas-containing solid systems for example microparticles (especially aggregates of microparticles) having gas contained therewithin or otherwise associated therewith (for example being adsorbed on the surface thereof and/or contained within voids, cavities or pores therein, e.g. as described in EP-A-0122624, EP-A-0123235 , EP-A- 0365467 , WO-A- 9
- microparticulate contrast agents may derive directly from the contained/associated gas and/or from gas (e.g. microbubbles) liberated from the solid material (e.g. upon dissolution of the microparticulate structure) .
- gas e.g. microbubbles
- Gas-containing microparticles preferably have an initial average size not exceeding 10 ⁇ m (e.g. of 7 ⁇ m or less) in order to permit their free passage through the pulmonary system following administration, e.g. by intravenous injection.
- phospholipid-containing contrast agents are employed in accordance with the invention, e.g. in the form of gas microbubbles stabilised by monolayers, bilayers or multiple layers of one or more phospholipids
- useful phospholipids include lecithins (i.e.
- phosphatidylcholines for example natural lecithins such as egg yolk lecithin or soya bean lecithin and synthetic or semisynthetic lecithins such as dimyristoylphosphatidylcholine , dipalmitoylphosphatidylcholine or distearoylphosphatidylcholine; phosphatidic acids; phosphatidylethanolamines ; phosphatidylserines ; phosphatidylglycerols ; phosphatidylinositols ; cardiolipins ,- sphingomyelins ; fluorinated analogues of any of the foregoing; mixtures of any of the foregoing and mixtures with other lipids such as cholesterol.
- natural lecithins such as egg yolk lecithin or soya bean lecithin
- synthetic or semisynthetic lecithins such as dimyristoylphosphatidylcholine ,
- the fatty acyl groups of such phospholipids will typically each contain about 14-22 carbon atoms, for example as in palmitoyl and stearoyl groups .
- Lyso forms of such phospholipids are useful in accordance with the invention, the term "lyso" denoting phospholipids containing only one fatty acyl groups, this preferably being ester-linked to the 1-position carbon atom of the glyceryl moiety.
- Such lyso forms may advantageously be used in admixture with phospholipids containing two fatty acyl groups .
- Phospholipid shells will in general tend to be relatively flexible, giving rise to microparticles with a relatively high susceptibility to ultrasonic pressure.
- microparticles comprising relatively hard and inflexible encapsulating shells
- gas- containing polymer microparticles wherein the polymer is a biodegradable polymer containing units of formula (I)
- microparticles comprise biodegradable polymers consisting of repeating units of formula (II)
- Contrast agents comprising gas microbubbles encapsulated by denatured and/or crosslinked protein (e.g. human serum albumin) shells, for example as described in WO-A-9217213 or WO-A-9406477, may also be useful examples of microparticles with relatively hard encapsulating shells.
- denatured and/or crosslinked protein e.g. human serum albumin
- gas-containing microparticles which may be useful in contrast agents according to the invention include carbohydrates (for example hexoses such as glucose, fructose or galactose; disaccharides such as sucrose, lactose or maltose; pentoses such as arabinose, xylose or ribose; - , ⁇ - and ⁇ -cyclodextrins ; polysaccharides such as starch, hydroxyethyl starch, amylose, amylopectin, glycogen, inulin, pulullan, dextran, carboxymethyl dextran, dextran phosphate, ketodextran, aminoethyldextran, alginates, chitin, chitosan, hyaluronic acid or heparin; and sugar alcohols, including alditols such as mannitol or sorbitol) , inorganic salts (e.g.
- X-ray contrast agents e.g. any of the commercially available carboxylic acid and non- ionic amide contrast agents typically containing at least one 2 , 4 , 6-triiodophenyl group having substituents such as carboxyl, carbamoyl , N-alkylcarbamoyl , N- hydroxyalkylcarbamoyl , acylamino, N-alkylacylamino or acylaminomethyl at the 3- and/or 5 -positions, as in metrizoic acid, diatrizoic acid, iothalamic acid, ioxaglic acid, iohexol , iopentol, iopamidol, iodixanol, iopromide, metrizamide, iodipamide, meglumine iodipamide, meglumine ace
- any biocompatible gas may be present in the microparticles, the term "gas" as used herein including any substances (including mixtures) substantially or completely in gaseous (including vapour) form at the normal human body temperature of 37°C.
- the gas may thus, for example, comprise air; nitrogen; oxygen; carbon dioxide; hydrogen; an inert gas such as helium, argon, xenon or krypton; a sulphur ' fluoride such as sulphur hexafluoride, disulphur decafluoride or trifluoromethylsulphur pentafluoride; selenium hexafluoride; an optionally halogenated silane such as methylsilane or dimethylsilane; a low molecular weight hydrocarbon (e.g.
- an alkane such as methane, ethane, a propane, a butane or a pentane, a cycloalkane such as cyclopropane, cyclobutane or cyclopentane, an alkene such as ethylene, propene, propadiene or a butene, or an alkyne such as acetylene or propyne; an ether such as dimethyl ether; a ketone; an ester; a halogenated low molecular weight hydrocarbon (e.g. containing up to 7 carbon atoms); or a mixture of any of the foregoing.
- an alkane such as methane, ethane, a propane, a butane or a pentane
- a cycloalkane such as cyclopropane, cyclobutane or cyclopentane
- an alkene such as ethylene, propene, propadiene or a butene
- biocompatible halogenated hydrocarbon gases may, for example, be selected from bromochlorodifluoromethane, chlorodifluoromethane , dichlorodifluoromethane , bromotrifluoromethane , chlorotrifluoromethane , chloropentafluoroethane , dichlorotetrafluoroethane , chlorotrifluoroethylene, fluoroethylene, ethylfluoride, 1, l-difluoroethane and perfluorocarbons, e.g.
- perfluoroalkanes such as perfluoromethane, perfluoroethane, perfluoropropanes, perfluorobutanes (e.g. perfluoro-n-butane, optionally in admixture with other isomers such as perfluoro-iso-butane) , perfluoropentanes, perfluorohexanes and perfluoroheptanes; perfluoroalkenes such as perfluoropropene, perfluorobutenes (e.g.
- perfluorobut-2- ene and perfluorobutadiene; perfluoroalkynes such as perfluorobut-2-yne ; and perfluorocycloalkanes such as perfluorocyclobutane , perfluoromethylcyclobutane , perfluorodimethylcyclobutanes , perfluorotrimethyl - cyclobutanes, perfluorocyclopentane, perfluoromethyl- cyclopentane, perfluorodimethylcyclopentanes, perfluorocyclohexane, perfluoromethylcyclohexane and perfluorocycloheptane .
- halogenated gases include methyl chloride, fluorinated (e.g. perfluorinated) ketones such as perfluoroacetone and fluorinated (e.g. perfluorinated) ethers such as perfluorodiethyl ether.
- perfluorinated gases for example sulphur hexafluoride and perfluorocarbons such as perfluoropropane, perfluorobutanes and perfluoropentanes, may be particularly advantageous in view of the recognised high stability in the bloodstream of microbubbles containing such gases .
- the same or different gases may be employed in the different types of microparticles.
- Contrast agent compositions and preparations in accordance with the invention may, for example, be prepared by appropriately admixing the different microparticle types.
- the microparticles and/or precursor forms thereof may be mixed in the dry state to give a product which may be formulated for administration by admixture with an appropriate aqueous carrier liquid such as sterile water for injection, or one or more of the microparticle types may be suspended or otherwise generated in an aqueous carrier liquid prior to such mixing.
- Aqueous preparations obtained in accordance with this latter embodiment may be used directly as contrast agents in accordance with the invention or may if desired be dried, for example by lyophilisation, to yield a storage-stable dried reconstitutable composition according to the invention.
- Phospholipid-stabilised microbubble suspensions for use in the above process may, for example, be prepared by generating a dispersion of gas microbubbles in an aqueous medium containing the phospholipid. This may, for example, be effected by subjecting the phospholipid- containing aqueous medium to any appropriate emulsion- generating technique, for example sonication, shaking, high pressure homogenisation, high speed stirring or high shear mixing, e.g. using a rotor-stator homogeniser, in the presence of the selected gas.
- any appropriate emulsion- generating technique for example sonication, shaking, high pressure homogenisation, high speed stirring or high shear mixing, e.g. using a rotor-stator homogeniser, in the presence of the selected gas.
- the aqueous medium may, if desired, contain additives which serve as viscosity enhancers and/or as solubility aids for the lipid, such as alcohols or polyols, e.g. glycerol and/or propylene glycol .
- the gas employed in the emulsification step need not be that desired in the final product . Thus most of this gas content may be removed during any subsequent lyophilisation step and residual gas may be removed by evacuation of the dried product, to which an atmosphere or overpressure of the desired end product gas may then be applied.
- the emulsification gas may therefore be selected purely to optimise the emulsification process parameters, without regard to end product considerations.
- Emulsification in the presence of a sulphur fluoride such as sulphur hexafluoride or a fluorinated low molecular weight hydrocarbon gas such as a perfluoroalkane or perfluorocycloalkane, preferably containing 4 or 5 carbon atoms, may be particularly advantageous in terms of ultimately yielding end products with consistent and narrowly distributed microbubble sizes.
- the emulsification is conveniently effected at about ambient temperature, e.g. at ca . 25 ⁇ 10°C. It may be necessary initially to heat the aqueous medium to facilitate hydration and thus dispersion of the lipid and then allow it to equilibrate to ambient temperature prior to emulsification.
- the resulting microbubble suspension may advantageously be subjected to one or more washing steps in order to separate and remove additives such as viscosity enhancers and solubility aids, as well as unwanted material such as non-gas-containing colloidal particles and undersized and/or oversized microbubbles. Such washing may be effected in per se known manner, the microbubbles being separated using techniques such as flotation or centrifugation. In this way size- fractionated microbubble dispersions may be prepared wherein at least 90% of the microbubbles have sizes within a 2 ⁇ m range, e.g. having a volume mean diameter within the range 2-5 ⁇ m.
- Any lyophilisation step may advantageously be conducted in the presence of one or more cryoprotective and/or lyoprotective and/or bulking agents, such agent (s) advantageously being added after any washing steps, prior to lyophilisation.
- cryoprotective and/or lyoprotective and/or bulking agents such agent (s) advantageously being added after any washing steps, prior to lyophilisation.
- Such agents include alcohols (e.g. aliphatic alcohols such as t-butanol) , polyols such as glycerol, aminoacids such as glycine, carbohydrates (e.g. sugars such as sucrose, mannitol, trehalose, glucose, lactose and cyclodextrins, or polysaccharides such as dextran) and polyglycols such as polyethylene glycol , the use of physiologically well- tolerated sugars such as sucrose (e.g. in an amount such as to render the product isotonic or somewhat hypertonic) being preferred.
- alcohols e.g. aliphatic alcohols such as t-butanol
- polyols such as glycerol
- aminoacids such as glycine
- carbohydrates e.g. sugars such as sucrose, mannitol, trehalose, glucose, lactose and cyclodextrins, or polysacc
- the mixed product may advantageously be filled into sealable vials prior to lyophilisation so as to give vials each containing an appropriate amount, e.g. a single dosage unit, of lyophilised dried product for reconstitution into an injectable form.
- an appropriate amount e.g. a single dosage unit
- the vials may be sealed with an appropriate closure.
- the lyophilised dried product may be reconstituted by addition of an appropriate injectable carrier liquid such as sterile pyrogen-free water or saline for injection.
- an appropriate injectable carrier liquid such as sterile pyrogen-free water or saline for injection.
- the dried product is contained in a vial this is conveniently sealed with a septum through which the carrier liquid may be injected using a syringe. It may be advantageous to mix or gently shake the product following reconstitution; no more than gentle hand-shaking may be required to give reproducible products with consistent microbubble size.
- the following non-limitative Example serves to illustrate the invention.
- hydrogenated egg phosphatidylserine 500.4 mg hydrogenated egg phosphatidylserine was added to 100 ml water containing 5.4% (w/w) of a mixture of propylene glycol and glycerol (3:10 w/w). The mixture was shaken and heated to 80 °C for five minutes, allowed to cool to room temperature, shaken again and left standing overnight prior to use .
- the solution was homogenised at 23000 rpm for 10 minutes, keeping the rotor stator mixing shaft such that the openings were slightly above the surface of the liquid.
- a white coloured creamy dispersion was obtained, which was transferred to a sealable container and flushed with perfluoro-n-butane .
- the dispersion was then transferred to a separating funnel and centrifuged at 12000 rpm for 30 minutes, yielding a creamy layer of bubbles at the top and a turbid infranatant .
- the infranatant was removed and replaced with water.
- the centrifugation was then repeated twice, but now at 12000 rpm for 15 minutes. After the last centrifugation, the supernatant was replaced by 10 % (w/w) sucrose.
- Gas-containing polymer microparticles prepared in accordance with any of Examples 3 (a) - (r) of WO-A-9607434 are added to vials containing the lyophilised product from Example 1(a) above, whereafter water for injection is added and the vials are gently hand-shaken for several seconds to give a contrast agent formulation according to the invention.
- water for injection is added to vials containing the lyophilised product from Example 1 (a) above and the vials are gently hand-shaken to give microbubble dispersions to which the gas-containing polymer microparticles according to any of Examples 3 (a) - (r) of WO-A-9607434 are added, either in dry form or as a dispersion in water for injection.
- the resulting mixture may be used directly as a contrast agent formulation in accordance with the invention or may be lyophilised to give a storage-stable dried product for subsequent reconstitution with an aqueous carrier such as water for injection.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9701237.1A GB9701237D0 (en) | 1997-01-22 | 1997-01-22 | Improvements in or relating to contrast agents |
GB9701237 | 1997-01-22 | ||
PCT/GB1998/000189 WO1998032468A1 (fr) | 1997-01-22 | 1998-01-22 | Agents de contraste contenant deux types de microbulles remplies de gaz |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0966305A1 true EP0966305A1 (fr) | 1999-12-29 |
Family
ID=10806374
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98900940A Ceased EP0966305A1 (fr) | 1997-01-22 | 1998-01-22 | Agents de contraste contenant deux types de microbulles remplies de gaz |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0966305A1 (fr) |
JP (1) | JP2001508454A (fr) |
CN (1) | CN1244131A (fr) |
AU (1) | AU5674098A (fr) |
CA (1) | CA2278750A1 (fr) |
GB (1) | GB9701237D0 (fr) |
NO (1) | NO993438L (fr) |
WO (1) | WO1998032468A1 (fr) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999013916A2 (fr) * | 1997-09-18 | 1999-03-25 | Nycomed Imaging As | Procedes et compositions pour l'imagerie medicale |
MXPA05007730A (es) | 2003-02-04 | 2006-01-31 | Bracco Int Bv | Agentes de contraste para ultrasonido y proceso para la preparacion de los mismos. |
US9750821B2 (en) | 2003-12-22 | 2017-09-05 | Bracco Suisse S.A. | Gas-filled microvesicle assembly for contrast imaging |
CN101005858A (zh) * | 2004-08-18 | 2007-07-25 | 伯拉考开发股份有限公司 | 用于反差成像的充气微泡组合物 |
WO2010010473A1 (fr) * | 2008-07-23 | 2010-01-28 | Koninklijke Philips Electronics, N.V. | Administration de médicament induite par les ultrasons |
CA2737026C (fr) | 2008-09-26 | 2019-12-24 | Ambrx, Inc. | Polypeptides d'erythropoietine animale modifies et leurs utilisations |
CN109529033A (zh) * | 2018-07-09 | 2019-03-29 | 彭盛 | 一种稳定的载氧微泡及其制备方法和应用 |
CN113521317B (zh) * | 2021-07-01 | 2023-03-31 | 中国科学院深圳先进技术研究院 | 一种双靶向肿瘤的超声分子复合成像方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5585112A (en) * | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
DE4100470A1 (de) * | 1991-01-09 | 1992-07-16 | Byk Gulden Lomberg Chem Fab | Echokontrastmittel |
ES2231775T5 (es) * | 1993-07-30 | 2011-02-02 | Imcor Pharmaceutical Co. | Composición de microburbujas estabilizadas para ecografía. |
GB9417941D0 (en) * | 1994-09-06 | 1994-10-26 | Nycomed Imaging As | Improvements in or relating to contrast agents |
-
1997
- 1997-01-22 GB GBGB9701237.1A patent/GB9701237D0/en active Pending
-
1998
- 1998-01-22 WO PCT/GB1998/000189 patent/WO1998032468A1/fr active Application Filing
- 1998-01-22 AU AU56740/98A patent/AU5674098A/en not_active Abandoned
- 1998-01-22 CN CN 98801948 patent/CN1244131A/zh active Pending
- 1998-01-22 JP JP53172098A patent/JP2001508454A/ja not_active Ceased
- 1998-01-22 CA CA002278750A patent/CA2278750A1/fr not_active Abandoned
- 1998-01-22 EP EP98900940A patent/EP0966305A1/fr not_active Ceased
-
1999
- 1999-07-13 NO NO993438A patent/NO993438L/no unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9832468A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP2001508454A (ja) | 2001-06-26 |
CN1244131A (zh) | 2000-02-09 |
NO993438D0 (no) | 1999-07-13 |
AU5674098A (en) | 1998-08-18 |
GB9701237D0 (en) | 1997-03-12 |
WO1998032468A1 (fr) | 1998-07-30 |
CA2278750A1 (fr) | 1998-07-30 |
NO993438L (no) | 1999-07-13 |
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NO318875B1 (no) | Ultralydkontrastmiddel |
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