EP1007103A2 - Process for preparation of lyophilised contrast agents - Google Patents
Process for preparation of lyophilised contrast agentsInfo
- Publication number
- EP1007103A2 EP1007103A2 EP98939754A EP98939754A EP1007103A2 EP 1007103 A2 EP1007103 A2 EP 1007103A2 EP 98939754 A EP98939754 A EP 98939754A EP 98939754 A EP98939754 A EP 98939754A EP 1007103 A2 EP1007103 A2 EP 1007103A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- gas
- chamber
- fluorocarbon
- microbubbles
- 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.)
- Withdrawn
Links
- 239000002872 contrast media Substances 0.000 title claims abstract description 64
- 238000000034 method Methods 0.000 title claims abstract description 47
- 230000008569 process Effects 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000004108 freeze drying Methods 0.000 claims abstract description 33
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000000463 material Substances 0.000 claims abstract description 20
- 238000009833 condensation Methods 0.000 claims abstract description 10
- 230000005494 condensation Effects 0.000 claims abstract description 10
- 239000002243 precursor Substances 0.000 claims abstract description 10
- 238000007789 sealing Methods 0.000 claims abstract description 8
- 239000006185 dispersion Substances 0.000 claims description 68
- 150000003904 phospholipids Chemical class 0.000 claims description 66
- KAVGMUDTWQVPDF-UHFFFAOYSA-N perflubutane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F KAVGMUDTWQVPDF-UHFFFAOYSA-N 0.000 claims description 32
- 229950003332 perflubutane Drugs 0.000 claims description 20
- 150000002632 lipids Chemical class 0.000 claims description 15
- 239000012298 atmosphere Substances 0.000 claims description 9
- 239000012736 aqueous medium Substances 0.000 claims description 7
- 150000008106 phosphatidylserines Chemical class 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 2
- 239000007789 gas Substances 0.000 description 149
- 239000000203 mixture Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 239000000047 product Substances 0.000 description 32
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 24
- 239000003570 air Substances 0.000 description 23
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 19
- 239000007788 liquid Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 15
- 238000003384 imaging method Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000009826 distribution Methods 0.000 description 14
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 13
- 239000002961 echo contrast media Substances 0.000 description 13
- 238000002604 ultrasonography Methods 0.000 description 12
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 11
- 239000002502 liposome Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 8
- 229960000909 sulfur hexafluoride Drugs 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 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 7
- 229930006000 Sucrose Natural products 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000012530 fluid Substances 0.000 description 7
- 235000013772 propylene glycol Nutrition 0.000 description 7
- 239000005720 sucrose Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 235000013601 eggs Nutrition 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- -1 polyoxyethylene Polymers 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 5
- 239000008365 aqueous carrier Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 238000004945 emulsification Methods 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000000787 lecithin Substances 0.000 description 5
- 235000010445 lecithin Nutrition 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000001694 spray drying Methods 0.000 description 5
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 229940039231 contrast media Drugs 0.000 description 4
- 230000000959 cryoprotective effect Effects 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000003019 stabilising effect Effects 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 229960003853 ultrasound contrast media Drugs 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000000232 Lipid Bilayer Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000002592 echocardiography Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000001924 fatty-acyl group Chemical group 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- QIYZKVMAFMDRTP-UHFFFAOYSA-N pentafluoro(trifluoromethyl)-$l^{6}-sulfane Chemical compound FC(F)(F)S(F)(F)(F)(F)F QIYZKVMAFMDRTP-UHFFFAOYSA-N 0.000 description 3
- 150000008103 phosphatidic acids Chemical class 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- QTJXVIKNLHZIKL-UHFFFAOYSA-N sulfur difluoride Chemical compound FSF QTJXVIKNLHZIKL-UHFFFAOYSA-N 0.000 description 3
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- 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 2
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 description 2
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- ABQLAMJAQZFPJI-UHFFFAOYSA-N 3-heptyloxolan-2-one Chemical compound CCCCCCCC1CCOC1=O ABQLAMJAQZFPJI-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- KLFKZIQAIPDJCW-HTIIIDOHSA-N Dipalmitoylphosphatidylserine Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCC KLFKZIQAIPDJCW-HTIIIDOHSA-N 0.000 description 2
- 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
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 241000183024 Populus tremula Species 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 239000003125 aqueous solvent Substances 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
- 230000037396 body weight Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
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- 235000012000 cholesterol Nutrition 0.000 description 2
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- 238000002059 diagnostic imaging Methods 0.000 description 2
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- 238000007667 floating Methods 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000002321 glycerophosphoglycerophosphoglycerols Chemical class 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 150000002576 ketones Chemical class 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
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- ZJIJAJXFLBMLCK-UHFFFAOYSA-N perfluorohexane Chemical class FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZJIJAJXFLBMLCK-UHFFFAOYSA-N 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- 229940067626 phosphatidylinositols Drugs 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
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- 239000003381 stabilizer Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
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- 231100000331 toxic Toxicity 0.000 description 2
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- 238000012285 ultrasound imaging Methods 0.000 description 2
- 229910052724 xenon Inorganic materials 0.000 description 2
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 2
- 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
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- WSJULBMCKQTTIG-OWOJBTEDSA-N (e)-1,1,1,2,3,4,4,4-octafluorobut-2-ene Chemical compound FC(F)(F)C(/F)=C(\F)C(F)(F)F WSJULBMCKQTTIG-OWOJBTEDSA-N 0.000 description 1
- 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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- ZVXOHSHODRJTCP-UHFFFAOYSA-N 1,1,2,2,3,3,4-heptafluoro-4-(trifluoromethyl)cyclobutane Chemical compound FC(F)(F)C1(F)C(F)(F)C(F)(F)C1(F)F ZVXOHSHODRJTCP-UHFFFAOYSA-N 0.000 description 1
- TXGPGHBYAPBDAG-UHFFFAOYSA-N 1,1,2,2,3,3-hexafluoro-4,4-bis(trifluoromethyl)cyclobutane Chemical class FC(F)(F)C1(C(F)(F)F)C(F)(F)C(F)(F)C1(F)F TXGPGHBYAPBDAG-UHFFFAOYSA-N 0.000 description 1
- YUFJLVUCHXMKKM-UHFFFAOYSA-N 1,1,2,2,3-pentafluoro-3,4,4-tris(trifluoromethyl)cyclobutane Chemical class FC(F)(F)C1(F)C(F)(F)C(F)(F)C1(C(F)(F)F)C(F)(F)F YUFJLVUCHXMKKM-UHFFFAOYSA-N 0.000 description 1
- ZVJOQYFQSQJDDX-UHFFFAOYSA-N 1,1,2,3,3,4,4,4-octafluorobut-1-ene Chemical class FC(F)=C(F)C(F)(F)C(F)(F)F ZVJOQYFQSQJDDX-UHFFFAOYSA-N 0.000 description 1
- LGPPATCNSOSOQH-UHFFFAOYSA-N 1,1,2,3,4,4-hexafluorobuta-1,3-diene Chemical compound FC(F)=C(F)C(F)=C(F)F LGPPATCNSOSOQH-UHFFFAOYSA-N 0.000 description 1
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 1
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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
Definitions
- This invention relates to the preparation of gas- containing contrast agents of use in diagnostic imaging. It is well known that ultrasonic imaging comprises a potentially valuable diagnostic tool, for example in studies of the vascular system, particularly in cardiography, and of tissue microvasculature .
- a variety of contrast agents has been proposed to enhance the acoustic images so obtained, including suspensions of solid particles, emulsified liquid droplets, gas bubbles and encapsulated gases or liquids. It is generally accepted that low density contrast agents which are easily compressible are particularly efficient in terms of the acoustic backscatter they generate, and considerable interest has therefore been shown in the preparation of gas-containing and gas-generating systems.
- Gas-containing contrast media are also known to be effective in magnetic resonance (MR) imaging, e.g. as susceptibility contrast agents which will act to reduce MR signal intensity.
- Oxygen-containing contrast media also represent potentially useful paramagnetic MR contrast agents .
- gases such as carbon dioxide may be used as negative oral contrast agents or intravascular contrast agents.
- radioactive gases e.g. radioactive isotopes of inert gases such as xenon
- scintigraphy for example for blood pool imaging .
- Initial studies involving free gas bubbles generated in vivo by intracardiac injection of physiologically acceptable substances have demonstrated the potential efficiency of such bubbles as contrast agents in echography; such techniques are severely limited in practice, however, by the short lifetime of the free bubbles .
- phospholipids as components of gas-containing ultrasound contrast agents.
- the use as ultrasound contrast media of phospholipid liposomes in which a lipid bilayer surrounds a confined composition including a gas or gas precursor is disclosed in US-A- 4900540.
- the encapsulated material is typically a gas precursor such as aqueous sodium bicarbonate, which is said to generate carbon dioxide following administration through exposure to body pH.
- the cores of the resulting liposomes will therefore tend to comprise liquid containing extremely small microbubbles of gas which will exhibit only limited echogenicity by virtue of their small size.
- WO-A-9115244 discloses ultrasound contrast media comprising microbubbles of air or other gas formed in a suspension of liquid- filled liposomes, the liposomes apparently stabilising the microbubbles. Such systems are differentiated from those of the above-mentioned US- A-4900540 in which the air or other gas is inside the liposomes .
- WO-A- 9211873 describes aqueous preparations designed to absorb and stabilise microbubbles and thereby serve as ultrasound contrast agents, the compositions comprising polyoxyethylene/polyoxypropylene polymers and negatively charged phospholipids.
- the weight ratio of polymer to phospholipid is typically about 3:1.
- Ultrasound contrast agents comprising gas-filled liposomes, i.e. liposomes which are substantially devoid of liquid in the interior thereof, and their preparation by a vacuum drying gas instillation method are described in WOA-9222247.
- the preparation of such gas-filled liposomes by a gel state shaking gas instillation method is described in WO-A-9428780.
- a report on gas-filled lipid bilayers composed of dipalmitoylphosphatidyl- choline as ultrasound contrast agents is presented by Unger et al . in Investigative Radiology 29, Supplement 2, S134-S136 (1994) .
- O-A-9409829 discloses injectable suspensions of gas microbubbles in an aqueous carrier liquid comprising at least one phospholipid stabiliser, the concentration of phospholipids in the carrier being less than 0.01% w/w but equal to or above the amount at which phospholipid molecules are present solely at the gas microbubble-liquid interface.
- the amount of phospholipid may therefore be as low as that necessary for formation of a single monolayer of surfactant around the gas microbubbles, the resulting film-like structure stabilising the bubbles against collapse or coalescence.
- Microbubbles with a liposome-like surfactant bilayer are said not to be obtained when such low phospholipid concentrations are used.
- O-A-9305819 proposes use of free microbubbles of gases having a coefficient Q greater than 5 where
- EP-A-0554213 suggests that one may impart resistance against collapse under pressure to gas-filled microvesicles by introduction thereto of at least one gas whose solubility in water, expressed in litres of gas/litres of water under standard conditions, divided by the square root of its molecular weight does not exceed 0.003.
- gases are said to include sulphur hexafluoride, selenium hexafluoride and various Freons ® .
- gases may, inter alia, be used in phospholipid-containing compositions of the type described in the above-mentioned O-A-9215244.
- WO-A-9503835 proposes use of microbubbles containing a gas mixture the composition of which is based on considerations of gas partial pressures both inside and outside the microbubbles, so as to take account of osmotic effects on microbubble size.
- Representative mixtures comprise a gas having a low vapour pressure and limited solubility in blood or serum (e.g. a fluorocarbon) in combination with another gas which is more rapidly exchanged with gases present in normal blood or serum (e.g. nitrogen, oxygen, carbon dioxide or mixtures thereof) .
- O-A-9516467 suggests use of ultrasound contrast media containing a mixture of gases A and B, where gas B is present in an amount of 0.5 - 41% v/v, has a molecular weight greater than 80 daltons and has aqueous solubility below 0.0283 ml/ml water under standard conditions, the balance of the mixture being gas A.
- Representative gases A include air, oxygen, nitrogen, carbon dioxide and mixtures thereof.
- Representative gases B include fluorine-containing gases such as sulphur hexafluoride and various perfluorinated hydrocarbons.
- Preferred stabilisers in such contrast media include phospholipids.
- Phospholipids said to be useful in prior art contrast agents 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, dipalmitoylphosphatidyl- choline or distearoylphosphatidylcholine; phosphatidic acids; phosphatidylethanolamines ; phosphatidylserines; phosphatidylglycerols; phosphatidylinositols; cardiolipins; sphingomyelins ; 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, dipalmitoylphosphatidyl- choline or distearoyl
- Lecithin derivatives generally appear to be the most commonly used phospholipids, possibly by virtue of their ready availability from natural sources.
- additives such as cholesterol in amounts of up to 50% w/w is disclosed in WO-A-9115244 and WO-A- 9409829, whilst the incorporation of at least a small amount (e.g. ca . 1 mole %) of negatively charged lipid (e.g. phosphatidylserine or a fatty acid) to enhance stability is suggested in O-A-9222247.
- a preferred phospholipid composition according to O-A-9428780 comprises dipalmitoylphosphatidylcholine, polyethylene- glycol 5000 -substituted dipalmitoylphosphatidylethanol- amine and dipalmitoylphosphatidic acid in molar proportions of about 87:8:5.
- Typical mixed phospholipid compositions according to O-A-9409829 and WO-A-9516467 comprise diarachidoylphosphatidylcholine and dipalmitoylphosphatidic acid in weight proportions of about 100:4, although the latter specification also exemplifies use of equal amounts by weight of distearoylphosphatidylcholine and dipalmitoyl- phosphatidylglycerol . It will be apparent from the foregoing that in existing phospholipid-containing microbubble suspensions proposed for use as contrast media, at least 50% of the phospholipid content comprises neutral phospholipids such as lecithins. Most commonly only a minor proportion, e.g. ca . 5%, of charged phospholipids is present .
- the use of charged phospholipids may enable the provision of microbubble contrast agents with advantageous properties regarding, for example, stability, dispersibility and resistance to coalescence without recourse to additives such as further surfactants and/or viscosity enhancers, thereby ensuring that the number of components administered to the body of a subject upon injection of the contrast agents is kept to a minimum.
- the charged surfaces of the microbubbles may minimise or prevent their aggregation as a result of electrostatic repulsion.
- a contrast agent for use in diagnostic studies comprising a suspension in an injectable aqueous carrier liquid of gas microbubbles stabilised by phospholipid- containing amphiphilic material characterised in that said amphiphilic material consists essentially of phospholipid predominantly comprising molecules with net charges .
- At least 75%, preferably substantially all of the phospholipid material in such contrast agents consists of molecules bearing a net overall charge under conditions of preparation and/or use, which charge may be positive or, more preferably, negative.
- Representative positively charged phospholipids include esters of phosphatidic acids such as dipalmitoylphosphatidic acid or distearoyl -phosphatidic acid with aminoalcohols such as hydroxyethylenediamine .
- Examples of negatively charged phospholipids include naturally occurring (e.g. soya bean or egg yolk derived), semisynthetic (e.g.
- phosphatidylserines phosphatidylglycerols , phosphatidylinositols , phosphatidic acids and cardiolipins .
- 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 charged phospholipids are also useful, the term "lyso" denoting phospholipids containing only one fatty acyl group, this preferably being ester-linked to the 1-position carbon atom of the glyceryl moiety.
- Such lyso forms of charged phospholipids may advantageously be used in admixture with charged phospholipids containing two fatty acyl groups .
- Phosphatidylserines represent particularly preferred phospholipids of use in such contrast agents and preferably constitute a substantial part, e.g. at least 80% of the initial phospholipid content thereof, for example 85-92%, although this may subsequently be reduced somewhat, e.g. to ca . 70%, in subsequent processing such as heat sterilisation. It will be appreciated that such processing may lead to formation of non-phospholipid degradation products such as free fatty acids, e.g. at levels of up to 10%; references herein to amphiphilic material consisting essentially of phospholipid are to be construed as embracing phospholipids containing such free fatty acids.
- phosphatidylserines include saturated (e.g. hydrogenated or synthetic) natural phosphatidylserine and synthetic or semi-synthetic dialkanoylphosphatidylserines such as distearoylphosphatidylserine, dipalmitoylphosphatidyl- serine and diarachidoylphosphatidylserine .
- phosphatidylserine-based contrast agents An important advantage of the use of such phosphatidylserine-based contrast agents is that the body recognises aged red blood cells and platelets by high concentrations of phosphatidylserine on their surface and so may eliminate such contrast agents from the blood stream in a manner similar to the elimination of red blood cells. Furthermore, since the surface of such contrast agents may be registered as endogenous by the body, they may avoid induction of adverse systemic side effects such as haemodynamic effects and other anaphylactic reactions which may accompany administration of some liposome preparations (see e.g. WO-A-9512386) . In support of this, no acute toxic effects such as changes in blood pressure or heart rate have been observed in animal tests on dogs injected with intravenous boluses of contrast agents according to W097/29783 at doses of up to ten times a normal imaging dose.
- gas includes 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; nitrous oxide; 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 tetramethylsilane; a low molecular weight hydrocarbon (e.g.
- an alkane such as methane, ethane, a propane, a butane or a pentane, a cycloalkane such as cyclobutane or cyclopentane, an alkene such as propene or a butene, or an alkyne such as acetylene; an ether; a ketone; an ester; a halogenated low molecular weight hydrocarbon
- biocompatible halogenated hydrocarbon gases may, for example, be selected from bromochlorodifluoromethane , chlorodifluoromethane, dichlorodifluoromethane , bromotrifluoromethane , chlorotrifluoromethane, chloropentafluoroethane, dichlorotetrafluoroethane and perfluorocarbons, e.g.
- perfluoroalkanes such as perfluoromethane, perfluoroethane, perfluoropropanes , perfluorobutanes (e.g. perfluoro-n-butane, optionally in admixture with other isomers such as perfluoroisobutane) , 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 , perfluorotrimethylcyclobutanes , perfluorocyclopentane , perfluoromethylcyclopentane, perfluorodimethylcyclopentanes , perfluorocyclohexane , perfluoromethylcyclohexane and perfluorocycloheptane .
- Other halogenated gases include fluorinated, e.g. perfluorinated, ketones such as perfluoroacetone and fluorinated, e.g. perfluorinated, ethers such as perfluorodiethyl ether.
- fluorinated gases such as sulphur fluorides or fluorocarbons (e.g. perfluorocarbons) which are known to form particularly stable microbubble suspensions (see, for example, the article by Schneider et al . referred to above) .
- Gas mixtures based on considerations of partial pressures both inside and outside the microbubbles and consequent osmotic effects on microbubble size e.g. as described in WO-A-9503835, may if desired be employed, for example a mixture of a relatively blood-soluble gas such as nitrogen or air and a relatively blood-insoluble gas such as a perfluorocarbon.
- contrast agents according to W097/29783 for example comprising microbubbles of a perfluoroalkane such as perfluorobutane stabilised by phosphatidylserine, are surprisingly stable in size following intravenous administration to a subject, and do not exhibit the previously described tendency of microbubbles of such gases to grow uncontrollably as a result of inward diffusion of blood gases such as oxygen, nitrogen and carbon dioxide, instead rapidly reaching a maximum size beyond which further growth is not observed. This avoidance of unlimited size increases which could lead to undesirable and potentially highly dangerous blocking of blood vessel capilliaries is a major advantage of such contrast agents .
- Contrast agents comprising perfluoroalkanes such as perfluorobutane have also been found to exhibit surprisingly high stability under pressures similar to those typically encountered in vivo, for example showing substantially complete (e.g. at least 90%) recovery to normal size distribution and echogenic properties after exposure to overpressures (e.g. of air) of up to 300mm Hg for 90 seconds.
- the contrast agents of W097/29783 may be used in a variety of diagnostic imaging techniques, including scintigraphy, light imaging, ultrasound, MR and X-ray (including soft X-ray) imaging. Their use in diagnostic ultrasound imaging and in MR imaging, e.g. as susceptibility contrast agents, constitute preferred features of the invention.
- a variety of imaging techniques may be employed in ultrasound applications, for example including fundamental and harmonic B-mode imaging and fundamental and harmonic Doppler imaging; if desired three-dimensional imaging techniques may be used.
- the contrast agent may also be used in ultrasound imaging methods based on correlation techniques, for example as described in US-A-5601085 and W097/12551. In vivo ultrasound tests in dogs have shown that such contrast agents may produce an increase in backscattered signal intensity from the myocardium of 15-25 dB following intravenous injection of doses as low as 1-20 nl microbubbles/kg body weight. Signals may be observed at even lower doses using more sensitive techniques such as colour Doppler or Doppler-derived techniques, e.g.
- Contrast agents according to W097/29783 may be produced with a very narrow size distribution for the microbubble dispersion within the range preferred for echocardiography, thereby greatly enhancing their echogenicity as well as their safety in vivo, and rendering the contrast agents of particular advantage in applications such as blood pressure measurements, blood flow tracing and ultrasound tomography.
- products in which over 90% e.g.
- the microbubbles have diameters in the range 1-7 ⁇ m and less than 5% (e.g. not more than 3%, preferably not more than 2%) of the microbubbles have diameters above 7 ⁇ m may readily be prepared.
- contrast agents may, for example, be administered in doses such that the amount of phospholipid injected is in the range 0.1-10 ⁇ g/kg body weight, e.g. 1-5 ⁇ g/kg in the case of fundamental B-mode imaging. It will be appreciated that the use of such low levels of phospholipid is of substantial advantage in minimising possible toxic side effects. Furthermore, the low levels of phospholipids present in effective doses may permit dosage increases to prolong observation times without adverse effects.
- the overall concentration of phospholipid in injectable forms of such contrast agents may conveniently be in the range 0.01-2%w/w, for example 0.2-0.8%w/w, advantageously about 0.5%w/w.
- contrast agents In general it is unnecessary to incorporate additives such as emulsifying agents and/or viscosity enhancers which are commonly employed in many existing contrast agent formulations into contrast agents according to W097/29783; this is of advantage in keeping to a minimum the number of components administered to the body of a subject and ensuring that the viscosity of the contrast agents is as low as possible. Since preparation of the contrast agents typically involves a freeze drying step as discussed in further detail hereinafter it may, however, be advantageous to include one or more agents with cryoprotective and/or lyoprotective effect and/or one or more bulking agents, for example an alcohol, e.g.
- an aliphatic alcohol such as t-butanol
- a polyol such as glycerol
- an aminoacid such as glycine
- a carbohydrate e.g. a sugar such as sucrose, mannitol, trehalose, glucose, lactose or a cyclodextrin, or a polysaccharide such as dextran; or a polyglycol such as polyethylene glycol .
- Prior art microbubble-containing contrast agents are typically prepared by contacting powdered surfactant, e.g. freeze- dried preformed liposomes or freeze-dried or spray-dried phospholipid solutions, with air or other gas and then with aqueous carrier, agitating to generate a microbubble suspension which must then be administered shortly after its preparation.
- powdered surfactant e.g. freeze- dried preformed liposomes or freeze-dried or spray-dried phospholipid solutions
- Contrast agents according to W097/29783 may advantageously be prepared by generating a gas microbubble dispersion in an appropriate phospholipid- containing aqueous medium, which may if desired previously have been autoclaved or otherwise sterilised, and thereafter subjecting the dispersion to lyophilisation to yield a dried reconstitutable product.
- the dried product contains one or more cryoprotective and/or lyoprotective agents it may, for example, comprise a microbubble-releasing cryoprotectant and/or lyoprotectant (e.g. carbohydrate) matrix containing gas-filled substantially spherical cavities or vacuoles surrounded by one or more layers of the amphiphilic material.
- Dried products so prepared are especially readily reconstitutable in aqueous media such as water, an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is not hypotonic) , or an aqueous solution of one or more tonicity-adjusting substances such as salts (e.g.
- microbubbles so generated is consistently reproducible and in practice is independent of the amount of agitational energy applied, being determined by the size of the microbubbles formed in the initial microbubble dispersion, this size parameter surprisingly being substantially maintained in the lyophilised and reconstituted product.
- process parameters such as the method, speed and duration of agitation, the final microbubble size may readily be controlled.
- Dried products so prepared have also proved to be storage stable for several months under ambient conditions.
- the microbubble dispersions generated upon reconstitution in water or an aqueous solution may be stable for at least 12 hours, permitting considerable flexibility as to when the dried product is reconstituted prior to injection.
- contrast agents comprising suspensions in an injectable aqueous carrier liquid of gas microbubbles stabilised by membrane-forming lipids, including both neutral and charged lipids (e.g. phospholipids) as well as mixtures thereof, and may be summarised as comprising the steps: i) generating a dispersion of gas microbubbles in an aqueous medium containing a membrane-forming lipid; ii) lyophilising the thus-obtained lipid- stabilised gas dispersion to yield a dried lipid- containing product; and iii) reconstituting the said dried product in an injectable aqueous carrier liquid.
- Step (i) may, for example, be effected by subjecting the lipid-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.
- 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 the subsequent lyophilisation step and residual gas may be removed by evacuation of the dried product, to which an atmosphere 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 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.
- Dispersions produced according to step (i) may advantageously be subjected to one or more washing steps prior to contrast agent use or to lyophilisation step (ii) , 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; the washed microbubble dispersions so obtained constitute a feature of the invention.
- Such washing may be effected in per se known manner, the microbubbles being separated using techniques such as flotation or centrifugation.
- microbubble dispersions with a particularly narrow size distribution represent important advantages of the process, especially since, as noted above, the resulting size distribution is substantially retained after lyophilisation and reconstitution.
- the dispersion from step (i) is frozen as quickly as possible, for example using a cooling medium such as liquid nitrogen. Accordingly it is particularly preferred to use a process comprising gas dispersion, washing/separation, rapid freezing, lyophilisation and reconstitution steps.
- Size-fractionated microbubble dispersions may be prepared wherein at least 90% of the microbubbles have sizes within a 2 ⁇ m range, the microbubbles preferably having a volume mean diameter within the range 2-5 ⁇ m.
- cryoprotective and/or lyoprotective agents may advantageously be added after the washing steps, prior to lyophilisation.
- Lyophilisation of the gas dispersion may, for example, be effected by initially freezing it and thereafter lyophilising the frozen gas dispersion, for example in per se generally known manner.
- the microbubbles may preferably be size fractionated prior to freezing, the released microbubbles preferably having a volume mean diameter within the range 2-5 ⁇ m.
- Such products may be stored frozen and thawed when desired, e.g. by simple warming and/or by addition of a carrier liquid, to regenerate microbubble dispersions useful as contrast agents .
- the gas dispersion 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 ability to select the end product gas content coupled with the ability independently to control the end product microbubble size by selection of appropriate process parameters during the initial dispersion step and any ensuing washing/separation step, enable the independent selection of microbubble size and gas content, thereby permitting the products to be matched to particular applications.
- the frozen gas dispersion or the dried product from step (ii) e.g.
- aqueous injectable carrier liquid such as sterile pyrogen-free water for injection, an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is not hypotonic) , or an aqueous solution of one or more tonicity-adjusting substances (e.g. as hereinbefore described) .
- a sterile aqueous injectable carrier liquid such as sterile pyrogen-free water for injection
- an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is not hypotonic)
- an aqueous solution of one or more tonicity-adjusting substances e.g. as hereinbefore described
- the size of the gas microbubbles may be substantially independent of the amount of agitational energy applied to the reconstituted dried product. Accordingly no more than gentle hand-shaking may be required to give reproducible products with consistent microbubble size.
- a desired gas such as a fluorocarbon
- this may be effected by feeding the desired gas into the lyophilisation chamber or an associated vacuum chamber containing the vials of lyophilised product, whereafter the vials may be stoppered or otherwise sealed and removed from the chamber.
- One embodiment of the present invention is based on the finding that such residual gases may advantageously be isolated in a separate condensation vessel prior to opening of the chamber to remove the vials.
- a process for the preparation of a fluorocarbon-containing lyophilised contrast agent which comprises lyophilising lyophilisable precursor material contained in one or more containers such as vials in a lyophilisation or like vacuum chamber, introducing said fluorinated gas into said chamber and effecting sealing closure of said container or containers, characterised in that, following closure of said container or containers, an overpressure of an atmospheric gas is applied to said chamber and said fluorocarbon gas is allowed to condense in a condensation vessel connected to said chamber.
- the invention further provides apparatus for use in the preparation of fluorocarbon-containing lyophilised contrast agents, which apparatus comprises a lyophilisation or like vacuum chamber adapted to receive one or more containers for lyophilisable precursor material, means for admitting fluorocarbon gas to said chamber, means for effecting sealing closure of said container (s) , means for applying an overpressure of atmospheric gas to said chamber, and a condensation vessel connectable to said chamber and adapted to receive and condense fluorocarbon gas remaining in said chamber after closure of said container (s) .
- the fluorocarbon gas may be as hereinbefore described, for example a perfluorocarbon such as perfluorobutane, and is desirably introduced into the apparatus through a sterile filter.
- a perfluorocarbon such as perfluorobutane
- the atmospheric gas may be air or a component thereof such as nitrogen, and is preferably sterilised.
- the use of an overpressure may be advantageous in maintaining closure of the container (s) , e.g. to prevent vial stoppers which have been inserted by a moving shelf assembly from sticking to the shelves as these are retracted from the closing position. Shelves in the moving shelf assembly are preferably coated in a non- stick material such as Teflon. The overpressure may also be maintained to assist in flushing residual fluorocarbon gas from the chamber.
- the condensation vessel may be the condensation unit of the lyophilisation apparatus, which after lyophilisation may be isolated from the chamber by means of an appropriate valve, heated (e.g. by steam) to melt the ice therein, drained, dried and cooled to a temperature below the boiling point of the fluorocarbon gas.
- the standard lyophilisation cooling circuit may itself give rise to a temperature within the condensation vessel below the boiling point of the fluorocarbon gas. However, if such a temperature is still above the boiling point further cooling can be achieved using liquid nitrogen or a dry ice/acetone cooling mixture.
- the isolating valve may be opened to allow fluorocarbon gas to diffuse to the cooling coil, condense and collect in a solvent tray.
- the condensed fluorocarbon may be fed to an evacuated flask which is continuously cooled to a temperature below the boiling point of the fluorocarbon and is connected to a drain point in the solvent tray.
- the feed vessel used to supply the fluorocarbon gas may itself be used as the condensation vessel .
- the vessel may be isolated from the chamber after introduction of the fluorocarbon gas, cooled (e.g. by immersion in liquid nitrogen) and reconnected to the chamber after sealing of the container (s) and application of atmospheric gas.
- an external condenser may be connected to the chamber, e.g. via a throttled vacuum pump. Since fluorinated gases are relatively heavy this should preferably be connected to the bottom of the chamber as far as possible from the atmospheric gas inlet .
- the condenser may, for example, comprise a vertically positioned cylindrical vessel having a plurality (e.g. three) inlets for fluorocarbon gas spaced around the periphery of its top surface to ensure diffuse entry of gas. The gas descends over a succession of staggered and optionally baffled circumferential cooling coils, condenses and collects at the bottom of the vessel, from where it may be transferred to an evacuated and cooled flask.
- the flask may be equipped with a cooling coil, preferably having enough turns to maintain the fluorocarbon in liquid form.
- a concentric axial outlet pipe fitted with drip catchers is positioned within the vessel above the collection zone and passes through the top surface of the vessel into the atmosphere.
- the recovered condensed fluorocarbon will preferably be subjected to purification (e.g. distillation) and/or sterilisation (e.g. filtration) procedures prior to reuse.
- the lyophilisable precursor material may, for example, comprise a dispersion of gas microbubbles in an aqueous medium containing a membrane-forming lipid, e.g. a phospholipid, preferably a negatively charged phospholipid such as a phosphatidylserine.
- lipid- stabilised gas microbubble-containing contrast agents may be prepared by spray drying procedures which may be simpler and less expensive to operate than the previously described emulsification/lyophilisation procedures and may also lead to efficient formation of substantially monosized microparticles .
- a contrast agent which comprises lipid-stabilised gas microbubbles wherein a solution or dispersion of said lipid is spray dried in an atmosphere of said gas.
- the lipid may, for example, be a phospholipid, preferably a negatively charged phospholipid such as a phosphatidylserine, and may be dissolved or dispersed in an aqueous solvent medium such as water for injection or an aqueous sucrose solution (e.g. such that the end product is isotonic) or an aqueous/organic solvent system such as chloroform/methanol/water, 2- butanol/water or tetrahydrofuran/water .
- an aqueous solvent medium such as water for injection or an aqueous sucrose solution (e.g. such that the end product is isotonic) or an aqueous/organic solvent system such as chloroform/methanol/water, 2- butanol/water or tetrahydrofuran/water .
- any appropriate gas e.g. as hereinbefore described, may be employed; the use of fluorinated gases, for example perfluorocarbons such as perfluorobutane, may be particularly advantageous. It will be appreciated that such gases should advantageously be used in a closed system, for example as in pharmaceutical spray drying apparatus manufactured by Niro A/S of Denmark.
- Gas-filled hollow microparticles prepared in accordance with such spray drying procedures may be filled directly into vials or like containers ready for reconstitution.
- the following non-limitative Examples serve to illustrate the invention.
- Fig. 1 represents a plot of percentage survival of volume concentration following lyophilisation and reconstitution against relative amount of charged phospholipid in the membranes of contrast agents according to Example 1 ;
- Fig. 2 represents plots of attenuation spectra for the frequency range 1.5-8 MHz of contrast agent according to Example 2 (a) measured a) before pressure testing, b) during pressure testing, and c) after pressure testing, as described in Example 6 ;
- Fig. 3 shows the percentage recovery in attenuation at 3.5 MHz of contrast agent according to Example 2(a) following 90 second applications of overpressures of 0- 300 mm Hg as described in Example 6;
- Fig. 4 shows volume size distributions for contrast agent according to Example 2 (a) measured by Coulter analysis a) without application of overpressure ( ⁇ ) , b) after 90 seconds of overpressure at 150 mm Hg ( ⁇ ) , and c) after 90 seconds of overpressure at 300 mm Hg ( ⁇ ) , as described in Example 6.
- Example 1
- Dispersions of microbubbles stabilised by different phospholipids or phospholipid mixtures were made according to the general procedure described below, using the process parameters given in Table 1.1 below.
- each vial was filled with perfluorobutane gas, and the vials were securely capped and shaken for 45 seconds using an Espe CapMix ® (mixer for dental materials) .
- the resulting microbubble dispersions were transferred to a larger vial and centrifuged at 2000 rpm for 5 minutes, giving a turbid infranatant below a floating layer of microbubbles.
- the infranatant was removed by a syringe and replaced with an equal volume of water at neutral pH .
- the washing step was repeated, but now the infranatant was replaced by 10 % (w/w) sucrose.
- the size distribution and volume concentration of the microbubbles were measured using a Coulter Counter Mark II apparatus fitted with a 50 ⁇ m aperture with a measuring range of 1-30 ⁇ m. 20 ⁇ l samples were diluted in 200 ml saline saturated with air at room temperature and allowed to equilibrate for 3 minutes prior to measurement . The measurements were made on microbubble dispersions prior to lyophilisation (washed bubble dispersion) and after lyophilisation (reconstituted with water to the same volume as before lyophilisation) . The data is presented in Table 1.2 below.
- the efficiency of lyophilisation for the different phospholipid stabilised microbubble dispersions was calculated as the percentage survival of the volume concentration following lyophilisation and reconstitution.
- a plot shows how this parameter varies with the relative amount of charged phospholipid in the membrane. As can be seen, the efficiency of lyophilisation increases with increased amount of charged phospholipid in the membrane, being highest for membranes containing charged phospholipids only.
- DPPE dipalmitoylphosphatidylethanolamine
- H-PC hydrogenated egg phosphatidylcholine
- H-PS hydrogenated egg phosphatidylserine
- DSPC distearoylphosphatidylcholine
- DSPG distearoylphosphatidylglycerol
- DPPA dipalmitoylphosphatidic acid. Table 1 . 2
- microbubble dispersions were combined in four larger vials and centrifuged at 2000 rpm for 5 minutes, giving a turbid infranatant below a floating layer of microbubbles .
- the infranatant was removed by a syringe and replaced with an equal volume of water at neutral pH. The washing step was repeated, but now the infranatant was replaced by 10% (w/w) sucrose. 2 ml portions of the resulting dispersion were divided between 10 ml flat-bottomed vials specially designed for lyophilisation, and the vials were cooled to -47°C and lyophilised for approximately 48 hours, giving a white fluffy solid substance.
- 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.
- 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.
- This solution was pumped through a 4 ml sonicator flow- through cell and exposed to ultrasound at 20 kHz with an amplitude of 90 ⁇ m.
- the diameter of the sonicator horn was 1.3 cm, the inner diameter of the cell was 2.1 cm and the distance between the horn and the bottom of the cell was 1 cm.
- the lipid solution was mixed with perfluoro-n-butane at a ratio of 1:2 v/v before it entered the sonicator cell (20 ml/min lipid solution and 40 ml/min perfluoro-n-butane gas) .
- the temperature was kept at 33°C. A white and creamy dispersion was obtained which was filled into a container and flushed with perfluoro-n-butane .
- the size distribution and volume concentration of the microbubbles were measured using a Coulter Counter Mark II apparatus fitted with a 50 ⁇ m aperture with a measuring range of 1-30 ⁇ m. 20 ⁇ l samples were diluted in 200 ml saline saturated with air at room temperature, and allowed to equilibrate for 3 minutes prior to measurement .
- Ultrasound characterisation was performed on a experimental set up slightly modified from de Jong, N. and Hoff, L. as described in "Ultrasound scattering properties of Albunex microspheres" , Ultrasonics 31 (3 ) , pp. 175-181 (1993) .
- This instrumentation measures the ultrasound attenuation efficacy in the frequency range 2-8 MHz of a dilute suspension of contrast agent.
- a pressure stability test was performed by exposing the sample to an overpressure of 120mm Hg for 90 seconds. Typically 2-3 ⁇ l of sample was diluted in 55 ml Isoton II and the diluted sample suspension was stirred for 3 minutes prior to analysis.
- the attenuation at 3.5 MHz was used, together with the recovery attenuation value at 3.5 MHz after release of the overpressure .
- Example 2 Two samples containing lyophilised product from Example 2 (b) were placed in a desiccator having a gas inlet and a gas outlet.
- the desiccator was connected to a B ⁇ chi 168 vacuum/distiller controller which permitted controlled evacuation of the samples and inlet of a selected gas .
- the samples were evacuated at approximately 10 mbar for 5 minutes, whereafter the pressure was increased to atmospheric by inlet of the selected gas, followed by careful capping of the vials The procedure was repeated using further pairs of samples for each of the selected gases.
- microbubble dispersions were characterised with respect to size distribution measurements as described in Example 2. The results are summarised in Table 3.1.
- Microbubbles containing sulphur hexafluoride, trifluoromethylsulphur pentafluoride or tetramethylsilane were only slightly less efficacious as Doppler enhancers than those containing perfluorobutane, giving integrals in the range 60-80% of the figure for perfluorobutane .
- Example 2 (b) 100 ml of the resulting solution was transferred to a round-bottomed flask with a conical neck and processed according to the procedure described in Example 2 (b) .
- a white coloured creamy dispersion was formed.
- This dispersion was transferred to a separating funnel and centrifuged at 12000 rpm for 30 minutes, yielding a creamy layer of microbubbles at the top and a turbid infranatant .
- the infranatant was removed and replaced with 50 ml water for injection. The centrifugation was then repeated twice, but now at 12000 rpm for 15 minutes.
- a vial containing lyophilised material under an atmosphere of perfluorobutane was prepared as described in Example 2 (b) . Water was added to the vial just before use to give a microbubble dispersion.
- the mean microbubble diameter was 1.77 ⁇ m and 0.25% of the microbubbles were larger than 5 ⁇ m.
- the corresponding values were 2.43 ⁇ m and 0.67%; repeated measurements made after a further 5 minutes indicated that the microbubble sizes had reached a stable value.
- Vials containing lyophilised material under an atmosphere of perfluorobutane were prepared as described in Example 2(a) .
- Water (2 ml) was added to the vials just before use to give microbubble dispersions.
- Attenuation spectra were recorded for 1.5-8 MHz before, during and after application of an overpressure of air at 300 mm Hg; the pressure was released after 90 seconds. The results are shown in Fig. 2 of the drawings, and indicate that although attenuation at 4
- Microbubbles are produced by spray drying a phospholipid dispersion comprising 1 mg/ml hydrogenated phosphatidylserine in a chlorofrom/methanol/water (100:20:0.1 v/v) mixture in a perfluorobutane atmosphere. After reconstitution with water the product shows echogenic properties.
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- 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)
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- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9717589.7A GB9717589D0 (en) | 1997-08-19 | 1997-08-19 | Improvements in or relating to contrast agents |
GB9717589 | 1997-08-19 | ||
PCT/GB1998/002491 WO1999008716A2 (en) | 1997-08-19 | 1998-08-19 | Process for preparation of lyophilised contrast agents |
Publications (1)
Publication Number | Publication Date |
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EP1007103A2 true EP1007103A2 (en) | 2000-06-14 |
Family
ID=10817734
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98939754A Withdrawn EP1007103A2 (en) | 1997-08-19 | 1998-08-19 | Process for preparation of lyophilised contrast agents |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1007103A2 (no) |
JP (1) | JP2001515055A (no) |
AU (1) | AU8816198A (no) |
GB (1) | GB9717589D0 (no) |
NO (1) | NO20000622L (no) |
WO (1) | WO1999008716A2 (no) |
ZA (1) | ZA987483B (no) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1228770B1 (en) * | 2001-01-31 | 2005-07-13 | Bracco Research S.A. | Lyophilisable contrast agent comprising gas microbubbles |
US9364569B2 (en) * | 2003-02-04 | 2016-06-14 | Bracco Suisse S.A. | Ultrasound contrast agents and process for the preparation thereof |
EP1701745B1 (en) | 2003-12-22 | 2014-12-10 | Bracco Suisse S.A. | Gas-filled microvesicle assembly for contrast imaging |
CA2575677C (en) | 2004-08-18 | 2013-01-22 | Bracco Research Sa | Gas-filled microvesicles composition for contrast imaging |
US9107950B2 (en) * | 2009-09-15 | 2015-08-18 | The Trustees Of Columbia University In The City Of New York | Systems, methods, and devices for microbubbles |
WO2013164269A1 (en) | 2012-04-30 | 2013-11-07 | Ge Healthcare As | Method for filling a container with a foamable composition |
GB201405735D0 (en) * | 2014-03-31 | 2014-05-14 | Ge Healthcare As | Ultrasound precursor preparation method |
GB201411423D0 (en) * | 2014-06-26 | 2014-08-13 | Ge Healthcare As | Lipid sterilisation method |
WO2023111332A1 (en) * | 2021-12-16 | 2023-06-22 | Bracco Suisse Sa | Method for extracting a fluorinated gas |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5469854A (en) * | 1989-12-22 | 1995-11-28 | Imarx Pharmaceutical Corp. | Methods of preparing gas-filled liposomes |
US5542935A (en) * | 1989-12-22 | 1996-08-06 | Imarx Pharmaceutical Corp. | Therapeutic delivery systems related applications |
US5773024A (en) * | 1989-12-22 | 1998-06-30 | Imarx Pharmaceutical Corp. | Container with multi-phase composition for use in diagnostic and therapeutic applications |
US5776429A (en) * | 1989-12-22 | 1998-07-07 | Imarx Pharmaceutical Corp. | Method of preparing gas-filled microspheres using a lyophilized lipids |
IL116328A (en) * | 1994-12-16 | 1999-09-22 | Bracco Research Sa | Frozen suspension of gas microbubbles in frozen aqueous carrier for use as contrast agent in ultrasonic imaging |
NZ331509A (en) * | 1996-02-19 | 2000-04-28 | Nycomed Imaging As | Aqueous dispersions of stabilised gas microbubbles and their use as contrast agents |
JP3634869B2 (ja) * | 1996-08-02 | 2005-03-30 | アメルシャム ヘルス アクスイェ セルスカプ | 造影剤における又はこれに関する改良 |
DE69718519T2 (de) * | 1996-09-11 | 2003-11-06 | Imarx Pharmaceutical Corp | Verbesserte verfahren zur diagnostischen bilderzeugung unter verwendung eines kontrastmittels und eines vasodilators |
-
1997
- 1997-08-19 GB GBGB9717589.7A patent/GB9717589D0/en active Pending
-
1998
- 1998-08-19 JP JP2000509452A patent/JP2001515055A/ja not_active Withdrawn
- 1998-08-19 WO PCT/GB1998/002491 patent/WO1999008716A2/en not_active Application Discontinuation
- 1998-08-19 AU AU88161/98A patent/AU8816198A/en not_active Abandoned
- 1998-08-19 ZA ZA987483A patent/ZA987483B/xx unknown
- 1998-08-19 EP EP98939754A patent/EP1007103A2/en not_active Withdrawn
-
2000
- 2000-02-08 NO NO20000622A patent/NO20000622L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO9908716A2 * |
Also Published As
Publication number | Publication date |
---|---|
JP2001515055A (ja) | 2001-09-18 |
WO1999008716A3 (en) | 1999-08-12 |
NO20000622L (no) | 2000-03-10 |
WO1999008716A2 (en) | 1999-02-25 |
ZA987483B (en) | 1999-05-21 |
NO20000622D0 (no) | 2000-02-08 |
GB9717589D0 (en) | 1997-10-22 |
AU8816198A (en) | 1999-03-08 |
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