JP6420761B2 - 気体マイクロバブルを含む組成物の調製 - Google Patents
気体マイクロバブルを含む組成物の調製 Download PDFInfo
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- JP6420761B2 JP6420761B2 JP2015519044A JP2015519044A JP6420761B2 JP 6420761 B2 JP6420761 B2 JP 6420761B2 JP 2015519044 A JP2015519044 A JP 2015519044A JP 2015519044 A JP2015519044 A JP 2015519044A JP 6420761 B2 JP6420761 B2 JP 6420761B2
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- protein
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- 239000000203 mixture Substances 0.000 title claims description 63
- 238000002360 preparation method Methods 0.000 title description 11
- 238000002156 mixing Methods 0.000 claims description 74
- 239000012460 protein solution Substances 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 61
- 102000004169 proteins and genes Human genes 0.000 claims description 40
- 108090000623 proteins and genes Proteins 0.000 claims description 40
- 239000007788 liquid Substances 0.000 claims description 32
- 239000002245 particle Substances 0.000 claims description 15
- 238000004925 denaturation Methods 0.000 claims description 14
- 230000036425 denaturation Effects 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 9
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 7
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000007789 gas Substances 0.000 description 118
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 17
- 238000012546 transfer Methods 0.000 description 17
- 238000009826 distribution Methods 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 229960004065 perflutren Drugs 0.000 description 9
- 239000002961 echo contrast media Substances 0.000 description 8
- 230000002093 peripheral effect Effects 0.000 description 8
- 230000032258 transport Effects 0.000 description 8
- 102000009027 Albumins Human genes 0.000 description 7
- 108010088751 Albumins Proteins 0.000 description 7
- 108010008908 FS 069 Proteins 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- -1 emulsified droplets Substances 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 238000004891 communication Methods 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000000084 colloidal system Substances 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 4
- 229960000909 sulfur hexafluoride Drugs 0.000 description 4
- 239000002872 contrast media Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- KAVGMUDTWQVPDF-UHFFFAOYSA-N perflubutane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F KAVGMUDTWQVPDF-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LGPPATCNSOSOQH-UHFFFAOYSA-N 1,1,2,3,4,4-hexafluorobuta-1,3-diene Chemical class FC(F)=C(F)C(F)=C(F)F LGPPATCNSOSOQH-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 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
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- 241000209149 Zea Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229950003332 perflubutane Drugs 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 2
- 229920002643 polyglutamic acid Polymers 0.000 description 2
- 230000008092 positive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
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- 239000003381 stabilizer Substances 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 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
- PWMJXZJISGDARB-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,5,5-decafluorocyclopentane Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F PWMJXZJISGDARB-UHFFFAOYSA-N 0.000 description 1
- BCNXQFASJTYKDJ-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,5-nonafluoro-5-(trifluoromethyl)cyclopentane Chemical compound FC(F)(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F BCNXQFASJTYKDJ-UHFFFAOYSA-N 0.000 description 1
- 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 compound 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 compound 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
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- RFCAUADVODFSLZ-UHFFFAOYSA-N 1-Chloro-1,1,2,2,2-pentafluoroethane Chemical compound FC(F)(F)C(F)(F)Cl RFCAUADVODFSLZ-UHFFFAOYSA-N 0.000 description 1
- ABQLAMJAQZFPJI-UHFFFAOYSA-N 3-heptyloxolan-2-one Chemical compound CCCCCCCC1CCOC1=O ABQLAMJAQZFPJI-UHFFFAOYSA-N 0.000 description 1
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
- 239000004340 Chloropentafluoroethane Substances 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 229910018503 SF6 Inorganic materials 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- MEXUFEQDCXZEON-UHFFFAOYSA-N bromochlorodifluoromethane Chemical compound FC(F)(Cl)Br MEXUFEQDCXZEON-UHFFFAOYSA-N 0.000 description 1
- RJCQBQGAPKAMLL-UHFFFAOYSA-N bromotrifluoromethane Chemical compound FC(F)(F)Br RJCQBQGAPKAMLL-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 235000019406 chloropentafluoroethane Nutrition 0.000 description 1
- AFYPFACVUDMOHA-UHFFFAOYSA-N chlorotrifluoromethane Chemical compound FC(F)(F)Cl AFYPFACVUDMOHA-UHFFFAOYSA-N 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- BPFZRKQDXVZTFD-UHFFFAOYSA-N disulfur decafluoride Chemical compound FS(F)(F)(F)(F)S(F)(F)(F)(F)F BPFZRKQDXVZTFD-UHFFFAOYSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- WBCLXFIDEDJGCC-UHFFFAOYSA-N hexafluoro-2-butyne Chemical compound FC(F)(F)C#CC(F)(F)F WBCLXFIDEDJGCC-UHFFFAOYSA-N 0.000 description 1
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 description 1
- WMIYKQLTONQJES-UHFFFAOYSA-N hexafluoroethane Chemical compound FC(F)(F)C(F)(F)F WMIYKQLTONQJES-UHFFFAOYSA-N 0.000 description 1
- HCDGVLDPFQMKDK-UHFFFAOYSA-N hexafluoropropylene Chemical class FC(F)=C(F)C(F)(F)F HCDGVLDPFQMKDK-UHFFFAOYSA-N 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- BCCOBQSFUDVTJQ-UHFFFAOYSA-N octafluorocyclobutane Chemical compound FC1(F)C(F)(F)C(F)(F)C1(F)F BCCOBQSFUDVTJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019407 octafluorocyclobutane Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229960004692 perflenapent Drugs 0.000 description 1
- 229960004624 perflexane Drugs 0.000 description 1
- LGUZHRODIJCVOC-UHFFFAOYSA-N perfluoroheptane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F LGUZHRODIJCVOC-UHFFFAOYSA-N 0.000 description 1
- ZJIJAJXFLBMLCK-UHFFFAOYSA-N perfluorohexane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZJIJAJXFLBMLCK-UHFFFAOYSA-N 0.000 description 1
- NJCBUSHGCBERSK-UHFFFAOYSA-N perfluoropentane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F NJCBUSHGCBERSK-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000012285 ultrasound imaging Methods 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012800 visualization Methods 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/248—Reactors comprising multiple separated flow channels
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00051—Controlling the temperature
- B01J2219/00074—Controlling the temperature by indirect heating or cooling employing heat exchange fluids
- B01J2219/00076—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements inside the reactor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/24—Stationary reactors without moving elements inside
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- General Preparation And Processing Of Foods (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Accessories For Mixers (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
Description
i)熱変性可能なタンパク質のタンパク質水溶液を初期変性を達成するのに必要な温度で用意するステップと、
ii)加熱されたタンパク質溶液からの熱によって気体を加熱するステップと、
iii)加熱された気体と加熱されたタンパク質溶液とを混合して気液混合物を得るステップと、
iv)気液混合物を機械的剪断力に付すことによって気体をタンパク質溶液中に分散せしめ、変性タンパク質で被包された気体マイクロバブルの組成物を生成するステップと
を標記の順序で含む。
i)2本の流路の各々の開口を与える第1の入口と第2の入口と、
ii)2本の流路を隔てる長手方向壁を含む伝熱部と、
iii)混合デバイスの入口と接続可能な1つの出口と
を含む。
i)高い機械的剪断力を生成し、入口と出口とを有する混合デバイスと、
ii)供給管であって、
2本の流路の各々の開口を与える第1の入口と第2の入口、
2本の流路を隔てる長手方向壁を含む伝熱部、及び
混合デバイスの入口に連結された1つの出口
を含む供給管と、
iii)供給管の第1の入口に連結された液体組成物用給液槽と、
iv)供給管の第2の入口に連結された気体槽と
を備える。
i)熱変性可能なタンパク質のタンパク質水溶液を初期変性を達成するのに必要な温度で用意するステップと、
ii)加熱されたタンパク質溶液からの熱によって気体を加熱するステップと、
iii)加熱された気体と加熱されたタンパク質溶液とを混合して気液混合物を得るステップと、
iv)気液混合物を機械的剪断力に付すことによって気体をタンパク質溶液中に分散せしめ、変性タンパク質で被包された気体マイクロバブルの組成物を生成するステップと
を標記の順序で含む。
六フッ化セレン、
テトラメチルシランなどの任意でハロゲン化されているシラン、
低分子量の炭化水素(例えば炭素原子を最高7個含むもの)、例えばメタン、エタン、プロパン、ブタンもしくはペンタンなどのアルカン、シクロブタンもしくはシクロペンタンなどのシクロアルカン、プロペンもしくはブテンなどのアルケン、又はアセチレンなどのアルキン、
エーテル、ケトン、エステル、
ハロゲン化低分子量炭化水素(例えば炭素原子を最高7個含むもの)、又はこれらの任意の混合物が含まれる。
i)2本の流路の各々の開口を与える第1の入口と第2の入口、
ii)2本の流路を隔てる長手方向壁を含む伝熱部、
iii)混合デバイスの入口と接続可能な1つの出口
を備える。
i)高い機械的剪断力を生成し、入口と出口とを有する混合デバイスと、
ii)供給管であって、2本の流路の各々の開口を与える第1の入口と第2の入口、2本の流路を隔てる長手方向壁を含む伝熱部、及び混合デバイスの入口に連結された1つの出口を備える供給管と、
iii)供給管の第1の入口に連結された液体組成物用給液槽と、
iv)供給管の第2の入口に連結された気体槽と
を備える。
本発明の方法により製造されたOptison(商標)のバッチを、信頼性及び予測可能性について評価し、第三者の方法と比較した。その目的は、2つの製造方法の予測可能性を比較して、製品品質の将来の予測可能性を理解することであった。
Optison(商標)のバッチを調製する25回の実験をGEヘルスケア社(GE Healthcare)が請求項記載の方法により製造し、Optison(商標)のバッチを調製する19回の実験を第三者の方法により製造し、信頼性及び予測可能性について評価を行い比較した。
2種類の方法で用いたパラメータを提供する生データを表1及び表2に示す。得られた平均粒径及び濃度が特定された。
平均粒径:SD 0.33μm
濃度:SD 1.19×108マイクロバブル/ml
請求項記載の方法:
平均粒径:SD 0.22μm
濃度:SD 0.55×108マイクロバブル/ml
標準偏差は製造時の再現性の増大を示すので、本発明の新規な改良方法を用いることによって製品の品質が向上すると予測される。
Claims (9)
- 気体封入マイクロバブルを含む組成物の調製方法であって、
i)熱変性可能なタンパク質の加熱されたタンパク質水溶液であって、初期変性を達成するのに必要な温度であって50〜100℃の範囲内の温度に加熱されたタンパク質水溶液を用意するステップと、
ii)加熱されたタンパク質溶液からの熱によって気体を加熱するステップであって、気体が、加熱されたタンパク質溶液の温度よりも20℃以内しか低くない温度に加熱されるステップと、
iii)ステップii)の加熱された気体とステップi)の加熱されたタンパク質溶液とを混合して加熱された気液混合物を得るステップと、
iv)ステップiii)の加熱された気液混合物を機械的剪断力に付すことによって加熱された気体をタンパク質溶液中に分散せしめ、変性タンパク質で被包された気体マイクロバブルの組成物を生成するステップと
を標記の順序で含む方法。 - ステップiii)の混合が、ステップiv)の機械的剪断力に付すために用いられる混合デバイスの入口又はその近傍で実施される、請求項1記載の方法。
- タンパク質溶液が一定の供給圧力下で供給される、請求項1又は請求項2記載の方法。
- 気体マイクロバブルが平均粒径の20%未満の標準偏差をもつ粒径を有する、請求項1乃至請求項3のいずれか1項記載の方法。
- タンパク質がヒト血清アルブミンである、請求項1乃至請求項4のいずれか1項記載の方法。
- 加熱されたタンパク質溶液の温度が60〜80℃の範囲内にある、請求項5記載の方法。
- 請求項1乃至請求項6のいずれか1項記載の方法を実施するのに適した装置であって、
i)高い機械的剪断力を生成し、入口と出口とを有する混合デバイス(20)と、
ii)供給管(30)であって、2本の流路の各々の開口を与える第1の入口(32)と第2の入口(34)、2本の流路を隔てる長手方向壁(31)を含む伝熱部、及び混合デバイス(20)の入口に連結された1つの出口(36)を備える供給管(30)と、
iii)熱交換器(68)を介して供給管(30)の第1の入口(32)に連結された液体組成物用給液槽(40)と、
iv)供給管(30)の第2の入口(34)に連結された気体槽(50)と
を備える装置(1)。 - 長手方向壁(31)が供給管(30)の管部に存在し、長手方向壁(31)が管部の直径を横断して2本の流路を形成する、請求項7記載の装置(1)。
- 長手方向壁(31)が供給管(30)の管部に存在し、管部が筒状外壁を有する外側管と内側管とを含み、内側管が外側管内部を貫通する、請求項7記載の装置(1)。
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