CN1035437A - 超声波造影剂及其制造方法和在诊断治疗中的应用 - Google Patents
超声波造影剂及其制造方法和在诊断治疗中的应用 Download PDFInfo
- Publication number
- CN1035437A CN1035437A CN89100726A CN89100726A CN1035437A CN 1035437 A CN1035437 A CN 1035437A CN 89100726 A CN89100726 A CN 89100726A CN 89100726 A CN89100726 A CN 89100726A CN 1035437 A CN1035437 A CN 1035437A
- Authority
- CN
- China
- Prior art keywords
- contrast agents
- ultrasonic contrast
- microgranule
- contain
- biolytic
- 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.)
- Granted
Links
- 239000002961 echo contrast media Substances 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- 239000004531 microgranule Substances 0.000 claims abstract description 25
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 229920001059 synthetic polymer Polymers 0.000 claims abstract description 11
- 229920000856 Amylose Polymers 0.000 claims abstract description 10
- 238000009835 boiling Methods 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 claims description 18
- 229920000642 polymer Polymers 0.000 claims description 17
- 239000007789 gas Substances 0.000 claims description 13
- -1 poly-alkyl cyanoacrylate Chemical compound 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 230000001804 emulsifying effect Effects 0.000 claims description 11
- 239000000178 monomer Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 10
- 239000003995 emulsifying agent Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 claims description 9
- 239000000839 emulsion Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229920001577 copolymer Polymers 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 7
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 229920001651 Cyanoacrylate Polymers 0.000 claims description 5
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 claims description 5
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 claims description 4
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012928 buffer substance Substances 0.000 claims description 4
- 239000006185 dispersion Substances 0.000 claims description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000003921 oil Substances 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- 229920000858 Cyclodextrin Polymers 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 3
- 229920000728 polyester Polymers 0.000 claims description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 3
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical group CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 claims description 3
- OEPOKWHJYJXUGD-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)-1,3-thiazole-4-carbaldehyde Chemical compound O=CC1=CSC(C=2C=C(OCC=3C=CC=CC=3)C=CC=2)=N1 OEPOKWHJYJXUGD-UHFFFAOYSA-N 0.000 claims description 2
- SDTLLOXEQAFNRQ-UHFFFAOYSA-N 3-(dimethylamino)-4-phenylbutan-2-one Chemical compound CN(C)C(C(C)=O)CC1=CC=CC=C1 SDTLLOXEQAFNRQ-UHFFFAOYSA-N 0.000 claims description 2
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical compound CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 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 claims description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 claims description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 2
- 239000001273 butane Substances 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000011243 crosslinked material Substances 0.000 claims description 2
- 150000001941 cyclopentenes Chemical class 0.000 claims description 2
- WMPOZLHMGVKUEJ-UHFFFAOYSA-N decanedioyl dichloride Chemical compound ClC(=O)CCCCCCCCC(Cl)=O WMPOZLHMGVKUEJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000003745 diagnosis Methods 0.000 claims description 2
- AZSZCFSOHXEJQE-UHFFFAOYSA-N dibromodifluoromethane Chemical compound FC(F)(Br)Br AZSZCFSOHXEJQE-UHFFFAOYSA-N 0.000 claims description 2
- 229930182830 galactose Natural products 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 239000004584 polyacrylic acid Substances 0.000 claims description 2
- 239000001294 propane Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims 2
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 claims 1
- 230000002209 hydrophobic effect Effects 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 16
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 14
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 12
- 238000004108 freeze drying Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000002872 contrast media Substances 0.000 description 6
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- 239000001110 calcium chloride Substances 0.000 description 5
- 229910001628 calcium chloride Inorganic materials 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 229920001992 poloxamer 407 Polymers 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000002601 radiography Methods 0.000 description 3
- 230000000717 retained effect Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 150000003504 terephthalic acids Chemical class 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 1
- JRHWHSJDIILJAT-UHFFFAOYSA-N 2-hydroxypentanoic acid Chemical compound CCCC(O)C(O)=O JRHWHSJDIILJAT-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 description 1
- 239000005792 Geraniol Substances 0.000 description 1
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229920000305 Nylon 6,10 Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- LUTSRLYCMSCGCS-BWOMAWGNSA-N [(3s,8r,9s,10r,13s)-10,13-dimethyl-17-oxo-1,2,3,4,7,8,9,11,12,16-decahydrocyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(=O)CC=C3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 LUTSRLYCMSCGCS-BWOMAWGNSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229960005233 cineole Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940113087 geraniol Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- A61K49/228—Host-guest complexes, clathrates, chelates
Abstract
本发明涉及由微粒制成的超声波造影剂，该微粒由直链淀粉或能被生物分解的合成聚合物和气体和/或沸点低于60℃的液体组成，以及这种超声波造影剂的制造方法及其在诊断治疗中的应用。
Description
本发明涉及由微粒制成的超声波造影剂及其制造方法和在诊断治疗中的应用。
公众已周，通过外围注射含有很小气泡的溶液，可以进行心脏的超声波造影（Roelandt J.Ultrasound Med.Biol.8∶471-492，1982）。这种气泡通过摇动、其他搅拌方法或加入二氧化碳等可保持在生理上能耐受的溶液中。但是由于气泡的数量和大小并不标准，所以它们不能充分地再生。而且通常都不稳定，致使它们存在的时间很短。它们的平均直径大多数均超过红血细胞的大小，因此不可能通过肺部毛细血管对左心脏、肝、肾或脾等器官进行造影。此外，由其所产生的超声回声是由许多互相不能分开的过程组成，例如气泡的形成、聚结和溶解，所以也不适宜于作定量表示。由于这些原因，采用这类超声波造影剂来测量造影过程，以获得心肌变换时间的诊断是不可能的。为此，需要有一种造影剂，其分散体不具有特殊的动力学。
其次，还有一种颗粒状超声波造影剂（Ophir，Gobuty，Mc Whirt，Maklad，Ultrasonic Backscatter from Contrast-producing Collagen Microspheres，Ultrasonic Imaging2∶66-67，1980）。此外，还有一种高密度溶液作为超声波造影剂使用（Ophir，Mc Whirt，Maklad，Aqueous Solutions with High Speed of Sound，Ultrasonic Imaging，3∶323-329，1981）。公众还知道，有一种可用作超声波造影剂的乳剂（Mattrey，Andre，Ultrasonic Enhancement of Myocardial Infarction with Perfluorcarbon Compounds in Dogs，AmJ.Cardiol54∶206-210，1984）.
由此可知，无气体造影剂的总数量也非常之少。含气体配制品的缺点是在体内的稳定性极差。此外，气泡的大小多数都不标准。在外周静脉注射后，在动脉血管系统中通常都不能获得充分的造影效果。
在EP A2123235和0122624两文中介绍了含气泡的超声波造影剂，这种造影剂可以通过肺部毛细血管。因此具有良好的造影效果。
EP A20224934介绍了充满气体的凝胶或清蛋白空心体的超声波造影剂。但其缺点是使用异体蛋白或变性本体蛋白，因而存在着与此相连系的过敏性反应的危险。
迄今所知，还没有一种超声波造影剂能够在静脉注射后通过选择性浓集在器官中获得稳定的信号，因此目前更不可能定量化。
本发明的任务是制造以微粒为基础的超声波造影剂，这种造影剂除了具有一定的能够再生的体积外，还比至今所知的造影剂具有更长的存在时间，没有潜在的过敏性危险，但具有良好的耐受性，能够注射到网状皮系细胞内，因此也能够浓集在肝脏或脾脏内。
本发明的这项任务是通过制取一种微粒得到解决的。这种微粒是由直链淀粉或一种能被生物分解的合成聚合物和一种气体和/或一种沸点低于60℃的液体组成。
能被生物分解的合成聚合物是α-、β-、δ-或ε-羟基碳酸的聚酯、聚烷基腈基丙烯酸酯、聚氨基酸、酰胺、聚丙烯酸糖化物或聚原酸酯。
特别适用的有：
聚乳酸，
聚-ε-己酸内酯，
乳酸和甘醇酸或己酸内酯的共聚物，
聚羟基丁酸，
聚羟基戊酸，
羟基丁酸和羟基戊酸的共聚物，
谷氨酸和/或赖氨酸的共聚物，
聚二慀烷酮，
氨基酸或/和对苯二酸、邻苯二甲酸或癸二酸的聚合物或共聚物，
聚丙烯葡聚糖，
聚丙烯淀粉，
聚丙烯酰胺，
聚氨基甲酸乙酯，
聚酯，
聚缩醛，
聚氨基三唑，或
聚烷基腈基丙烯酸酯。
微粒中可含有淀粉或淀粉衍生物。采用直链淀粉是适宜的，因为这种淀粉衍生物易溶于水并能形成笼形化合物。
特别适用的直链淀粉是环糊精及其衍生物，例如α-、β-和δ-环糊精。
微粒中含有游离的或结合形式的气体和/或沸点低于60℃的液体。同样也可在超声波造影剂中采用气液混合物。
气体可以采用空气、氮气、稀有气体、氢气、二氧化碳、氨气、氧气、甲烷、乙烷、丙烷、丁烷、乙烯或其他烃类或它们的混合物等。
优先采用下列液体或它们的混合物：
1，1-二氯乙烯，
2-甲基-2-丁烯，
2-氯丙烷，
2-甲基-1，3-丁二烯，
2-丁炔，
2-甲基-1-丁烯，
二溴二氟甲烷，
呋喃，
3-甲基-1-丁烯，
异戊烷，
二乙醚，
3，3-二甲基-1-丁炔，
二甲基氨基丙酮，
氧化丙烯，
N-乙基甲胺，
溴甲烷，
N-乙基二甲胺，
二氯甲烷，
戊烷，
环戊烷，
2，3-戊二烯，
环戊烯。
微粒也可含有低蒸汽压和/或低沸点的物质，尤指挥发性油类，这样更为有利。
特别有利的是由直链淀粉组成的带有包层物质的微粒，这种微粒由油、脂肪和/或表面活性物质包层并悬浮在水介质中。
由直链淀粉组成的微粒用基质，尤用聚合物结构的基质包层特别有利。
通过加入渗透活性物质，例如食盐、甘露糖醇、半乳糖、葡萄糖、果糖、可以调整生理等渗性。
本发明还涉及由生物可分解的合成聚合物组成的超声波造影剂的制造方法。
制造本发明超声波造影剂的优良方法是将聚合物或共聚物溶于一种或多种与水不能混合的有机溶剂中，如需要，在接着将另一种溶剂加入水后进行乳化，过滤所得乳剂，必要时还可进行干燥。
另一个制造方法是将聚合物或共聚物溶于一种或多种含气泡的溶剂中，如需要，在接着加入另一种溶剂或另一种聚合物后，进行沉淀或在水中乳化，然后过滤所得悬浮液或乳剂，必要时还可进行干燥。为了便于加工，可进行冰冻干燥处理。
最好将所得产品磨成很细的粉末。
上述两种方法所用的溶剂有：呋喃、戊烷、丙酮、二慀烷、乙酸乙酯、二甲苯、二氯甲烷、环己烷或己烷，或溶剂混合物等。乳剂中也可加入乳化剂。
另一种制造方法则不是从聚合物着手，而是由构成聚合物的单体着手。在这种情况下，将单体溶于一种或几种有机溶剂中，并在5-30份水中或0.01-0.1N盐酸中（需要时可加入乳化剂或缓冲物质），在低于有机溶剂沸点的温度条件下进行乳化，再将第二种单体的0.2%-20%水溶液加入该乳剂，或需要时可加入pH值较高的物质，必要时还可进行干燥。
另一种处理方法是将单体溶解或分散于一种或多种含气泡液体中，必要时可加入乳化剂或缓冲物质，如有需要，还可将第二种单体的0.2%-20%溶液或溶解状态或气体状态的高pH物质，加入该溶液或分散体中，必要时可进行干燥。
例如，第一种单体可用对苯二酰氯或癸二酰氯或腈基丙烯酸酯，第二种单体可用L-赖氨酸，有机溶剂可用2-甲基-1，3-丁二烯、二慀烷、二氯甲烷、甲苯或环己烷等。
按另一种方法，超声波造影剂的制取可以在0.5-10%的单体水溶液或分散体中产生气泡，必要时加入0.01-5%的乳化剂或0.1-5%准乳化剂，然后加入交联物质和/或反应起动剂。
上述超声波造影剂可以用于诊断或治疗的方法。
可以通过注射等方法使用本发明的造影剂。
本发明通过下列实施例予以说明：
实施例1
将500mg聚交酯溶于4ml呋喃和0.6ml环己烷，再将该溶液在40ml的分子量为12000的0.1%聚氧乙烯聚氧丙烯聚合物（Pluronic
F127）溶液中乳化，乳化期间的温度保持在15℃以下。然后将温度缓慢升高，使有机溶剂蒸发，接着将生成的悬浮液冰冻干燥。
实施例2
将300mgα-腈基丙烯酸丁酯溶于1ml呋喃中，再将该溶液在10ml含有分子量为12000的1%聚氧乙烯聚氧丙烯聚合物（Pluronic
F127）的0.1N盐酸中乳化，乳化期间的温度保持在15℃以下。聚合结束后，将生成的悬浮液冰冻干燥。
实施例3
将200mgα-腈基丙烯酸丁酯溶于0.4ml异戊二烯，再在30ml含有分扛量为8350的1%聚氧乙烯聚氧丙烯聚合物（Pluronic
F68）的0.01N盐酸中乳化，乳化期间的温度保持在10℃以下。聚合结束后，悬浮液用0.1NNaOH中和并用氯化钠使之达到等渗浓度。
实施例4
将400mgα-腈基丙烯酸丁酯溶于0.4ml二氯甲烷，再在60ml含有12000分子量的1%聚氧乙烯聚氧丙烯聚合物（Pluronic
F127）的0.01N盐酸中乳化，乳化期间的温度保持在10℃以下。聚合结束后，悬浮液用0.1N NaOH中和，用氯化钠使之达到等渗浓度。
实施例5
将400mg聚己酸内酯溶于6ml呋喃和0.3ml环己烷，再在60ml含有分子量为12000的1%聚氧乙烯聚氧丙烯聚合物（Pluronic
F127）中乳化，温度保持在15℃以下。然后将温度缓慢升高，使有机溶剂蒸发。接着将生成的悬浮液冰冻干燥。
实施例6
将400ml对苯二酸二氯化物溶于2ml呋喃中，再在50ml含分子量12000的0.1%聚氧乙烯聚氧丙烯聚合物（Pluronic
F127）的3%碳酸钠溶液液中乳化。加入60mg L-赖氨酸后，溶于5ml 0.1%的Pluronic F127中，离心微胶囊，再用0.1%Pluronic F127溶液洗涤数次。使用前，用氯化钠使悬浮液达到等渗浓度。
实施例7
β-环糊精-异戊烷笼形化合物：
将100ml饱和β-环糊精溶液（1.8%）冷却至10℃，再加入3ml异戊烷。在超声浴中不断搅拌下，析出生成的难溶解复合物。通过冰冻干燥和过滤，得到结晶沉淀物。根据气相色谱测定，含异戊烷0.26%。
实施例8
β-环糊精-2-甲基-2-丁烯笼形化合物：
将100ml饱和β-环糊精溶液（1.8%）冷却至10℃，再加入3ml 2-甲基-2-丁烯。在超声浴中不断搅拌下，析出生成的难溶解复合物。通过冰冻干燥和过滤，得到结晶沉淀物。
实施例9
β-环糊精-2-甲基-1-丁烯笼形化合物：
将100ml饱和β-环糊精溶液（1.8%）冷却至10℃，再加入3ml 2-甲基-1-丁烯。在超声浴中不断搅拌下，析出生成的难溶解复合物。通过冰冻干燥和过滤，得到结晶沉淀物。根据气相色谱测定，含2-甲基-1-丁烯0.82%。
实施例10
β-环糊精-异戊二烯笼形化合物：
将100ml饱和β-环糊精溶液（1.8%）冷却至10℃，再加入3ml异戊二烯。在超声浴中不断搅拌下，析出生成的难溶解复合物。通过冰冻干燥的过滤，得到结晶沉淀。根据气相色谱测定，含异戊二烯1.0%。
实施例11
β-环糊精-2-氯丙烷笼形化合物：
将100ml饱和β-环糊精溶液（1.8%）冷却至10℃，再加入3ml 2-氯丙烷。在超声浴中不断搅拌下，析出生成的难溶解复合物。通过冰冻干燥和过滤，得到结晶沉淀物。根据气相色谱测定，含2-氯丙烷0.5%。
实施例12
β-环糊精异戊烷笼形化合物：
将100ml饱和β-环糊精溶液（1.8%）冷却至10℃，再加入3ml异戊烷。在超声浴中不断搅拌下，析出生成的难溶解复合物。通过冰冻干燥和过滤，得到结晶沉淀物。
实施例13
氙/α-环糊精笼形化合物：
在7个大气压的氙和室温条件下，将100ml饱和α-环糊精溶液（约12%）置于200cm3高压釜中保温7天。吸出结晶加成物，用冷水洗涤，在氯化钙干燥器中干燥。
实施例14
二氧化碳/α-环糊精笼形化合物：
在7个大气压二氧化碳和室温条件下，将100ml饱和α-环糊精溶液（约12%）置于20cm3高压釜中保温7天。吸出结晶加成物，用冷水洗涤，在氯化钙干燥器中干燥。
实施例15
异戊烷/羟丙基-β-环糊精笼形化合物：
在10℃下，将2ml异戊烷加入10ml的20%羟丙基-β-环糊精溶液。在超声浴中处理3分钟，然后保温26小时，生成的复合物仍保留在溶液中。
实施例16
异戊二烯/羟丙基-β-环糊精笼形化合物：
在10℃下，将2ml异戊二烯加入15ml的20%羟丙基-β-环糊精溶液中，在超声浴中处理3分钟，然后保温26小时，生成的复合物部分仍保留在溶液中，部分则作为白色沉淀物沉淀。
实施例17
呋喃/羟丙基-β-环糊精笼形化合物：
在10℃下，将2ml呋喃加入15ml的20%羟丙基-β-环糊精溶液中，在超声浴中处理3分钟，然后保温26小时。生成的复合物部分得保留在溶液中，部分则作为白色沉淀物沉淀。
实施例18
异戊烷/α-环糊精笼形化合物：
将1ml异戊烷加入20ml饱和α-环糊精溶液中，在超声浴中处理3分钟。过滤得到生成的难溶解复合物，再用氯化钙干燥。
实施例19
异戊二烯/α-环糊精笼形化合物：
将1ml异戊二烯加入20ml饱和α-环糊精溶液中，在超声浴中处理3分钟。过滤得到生成的难溶解复合物，再用氯化钙干燥。
实施例20
呋喃/α-环糊精笼形化合物：
将1ml呋喃加入20ml饱和α-环糊精溶液中，在超声浴中处理3分钟。过滤得到生成的难溶解复合物，再用氯化钙干燥。
以下适用于实施例7-20：
结晶沉淀物在适当的水介质中纯化后，优先采用生理盐水、葡萄糖溶液或环状化合物溶液纯化，然后制成注射剂。
实施例21
在超声浴中进行超声处理条件下，将4g桉油醇滴加到100mlα-环糊精溶液（5℃）的保温容器中，继续超声处理30分钟。然后置于冷却封闭的容器中摇动48小时，过滤得到生成的沉淀物，用冷乙醇洗涤，经液氮冰冻干燥。
实施例22
将2g牻牛儿醇加入100mlα-环糊精溶液中，在5℃下，在超声浴中超声波处理4小时，然后在5℃下保温24小时。过滤得到生成的沉淀物，用冷乙醇洗涤，再在液氮中冰冻干燥。
Claims (18)
1、由微粒组成的超声波造影剂，其特征在于该微粒由直链淀粉和沸点在60℃以下的有机液体或由能被生物分解的合成聚合物和气体和/或沸点在60℃以下的液体组成。
2、按权利要求1的超声波造影剂，其特征在于该微粒含有直链淀粉环糊精或环糊精衍生物。
3、按权利要求1的超声波造影剂，其特征在于该微粒含有作为能被生物分解的合成聚合物的有：α-、β-、δ-或ε-羟基碳酸的聚酯、聚烷基腈基丙烯酸酯、聚氨基酸、酰胺、聚丙烯酸糖化物或聚原酸酯。
4、按权利要求1至3中至少一项所述的超声波造影剂，其特征在于含有沸点低于60℃的下列有机液体或其混合物：
1，1-二氯乙烯，
2-甲基-2-丁烯，
2-氯丙烷，
2-甲基-1，3-丁二烯，
2-丁炔，
2-甲基-1-丁烯，
二溴二氟甲烷，
呋喃，
3-甲基-1-丁烯，
异戊烷，
二乙醚，
3，3-二甲基-1-丁炔，
二甲基氨基丙酮，
氧化丙烯，
N-乙基甲胺，
溴甲烷，
N-乙基二甲胺，
二氯甲烷，
戊烷，
环戊烷，
2，3-戊二烯，
环戊烯。
5、按权利要求1至3中至少一项所述的超声波造影剂，其特征在于该微粒含有下列气体或其混合物：
空气，
稀有气体，
氮气，
氧气，
二氧化碳，
氢气，
氨，
乙烯，
甲烷，
乙烷，
丙烷，或
丁烷。
6、按权利要求1的超声波造影剂，其特征在于该微粒含有挥发性油类。
7、按权利要求1，2和4至6中至少一项所述的超声波造影剂，其特征在于由直链淀粉组成的微粒具有由油类、脂肪和/或表面活性物质包层并悬浮在水介质中的疏水包层物质。
8、按权利要求1、2和4至7中至少一项所述的超声波造影剂，其特征在于由直链淀粉组成的微粒由基质，特别是具有聚合物结构的基质包层。
9、按权利要求1至8中至少一项所述的超声波造影剂，其特征在于通过加入渗透活性物质，特别是通过加入食盐、甘露糖醇、半乳糖、葡萄糖、果糖，调整生理等渗性。
10、含由按权利要求1或3至5之一的能被生物分解的合成聚合物组成的微粒的超声波造影剂的制造方法，其特征在于聚合物或共聚物溶于一种或多种与水不相混合的有机溶剂中，过滤所得乳剂，需要时再进行干燥。
11、含由按权利要求1或3至5之一的能被生物分解的合成聚合物组成的微粒的超声波造影剂的制造方法，其特征在于聚合物或共聚物溶于一种或多种含气泡的溶剂中，必要时在加入另一种溶剂或另一种聚合物后折出或在水中乳化，过滤所得悬浮液或乳剂，需要时再进行干燥。
12、按权利要求10或11的方法，其特征在于用作溶剂的有呋喃、戊烷、丙酮、二噁烷、乙酸乙酯、二甲苯、二氯甲烷、环己烷或己烷，或由上述溶剂组成的混合物。
13、按权利要求10或11的方法，其特征在于在乳剂中加入乳化剂。
14、含由按权利要求1和/或3至6之一的能被生物分解的合成聚合物组成的微粒的超声波造影剂的制造方法，其特征在于单体溶于一种或多种有机溶剂中，并在5-30份水或0.01-0.1N盐酸中，需要时可加入乳化剂或缓冲物质，在低于有机溶剂沸点的温度条件下进行乳化，再将第一种单体的0.2%-20%水溶液加入该乳剂中，或需要时加入pH值较高的物质，必要时还可进行干燥。
15、含由按权利要求1和/或3至6之一的能被生物分解的合成聚合物组成的微粒的超声波造影剂的制造方法，其特征在于单体溶解或分散于一种或多种含有气泡的液体中，必要时可加入乳化剂和/或缓冲物质，如有需要，还可将第二种单体的0.2%-20%溶液或溶解状态或气体状态的高pH物质加入该溶液或分散体中，必要时可进行干燥。
16、按权利要求14或15的方法，其特征在于所用第一种单体是对苯二酰氯或癸二酰氯或腈基丙烯酸酯，所用第二种单体是L-赖氨酸，所用有机溶剂是2-甲基-1，3-丁二烯、二氯甲烷、甲苯、二噁烷或环己烷。
17、含由按权利要求1和/或3至6之一的能被生物分解的合成聚合物组成的微粒的超声波造影剂的制造方法，其特征在于在0.5-10%的单体水溶液中产生气泡，必要时加入0.01-5%的乳化剂或0.1-5%准乳化剂，然后加入交联物质和/或反应起动剂。
18、权利要求1至9之一的超声波造影剂在诊断或治疗方法中的应用。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3803972.9 | 1988-02-05 | ||
| DEP3803971.0 | 1988-02-05 | ||
| DE3803972A DE3803972A1 (de) | 1988-02-05 | 1988-02-05 | Ultraschallkontrastmittel |
| DE3803971A DE3803971C2 (de) | 1988-02-05 | 1988-02-05 | Ultraschallkontrastmittel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1035437A true CN1035437A (zh) | 1989-09-13 |
| CN1033840C CN1033840C (zh) | 1997-01-22 |
Family
ID=25864722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN89100726A Expired - Fee Related CN1033840C (zh) | 1988-02-05 | 1989-02-04 | 制备用于超声造影的微粒和超声波造影剂的方法 |
Country Status (20)
| Country | Link |
|---|---|
| US (3) | US6264959B1 (zh) |
| EP (3) | EP0398935B1 (zh) |
| JP (2) | JP2907911B2 (zh) |
| KR (1) | KR0133132B1 (zh) |
| CN (1) | CN1033840C (zh) |
| AT (1) | ATE109663T1 (zh) |
| AU (1) | AU635200B2 (zh) |
| CA (1) | CA1336164C (zh) |
| DE (1) | DE58908194D1 (zh) |
| DK (1) | DK175832B1 (zh) |
| ES (1) | ES2068917T3 (zh) |
| FI (1) | FI99086C (zh) |
| HU (1) | HU221485B (zh) |
| IE (2) | IE66912B1 (zh) |
| IL (1) | IL89175A (zh) |
| MY (1) | MY105856A (zh) |
| NO (2) | NO301260B1 (zh) |
| NZ (1) | NZ227869A (zh) |
| PT (1) | PT89635B (zh) |
| WO (1) | WO1989006978A1 (zh) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1064851C (zh) * | 1992-06-13 | 2001-04-25 | 舍林股份公司 | 微粒，其制造方法以及在诊断中的应用 |
| CN1066963C (zh) * | 1993-03-16 | 2001-06-13 | 奈科姆成像有限公司 | 造影剂及其改进 |
| CN1068230C (zh) * | 1993-01-25 | 2001-07-11 | 索纳斯药品有限公司 | 用作超声造影剂的相转变胶体 |
| CN104994800A (zh) * | 2013-03-29 | 2015-10-21 | 奥林巴斯株式会社 | 超声波治疗装置 |
Families Citing this family (155)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4219724A1 (de) * | 1992-06-13 | 1993-12-16 | Schering Ag | Verwendung von Mikrokapseln als Kontrastmittel für die Farbdoppler-Sonographie |
| US5425366A (en) * | 1988-02-05 | 1995-06-20 | Schering Aktiengesellschaft | Ultrasonic contrast agents for color Doppler imaging |
| US6088613A (en) | 1989-12-22 | 2000-07-11 | Imarx Pharmaceutical Corp. | Method of magnetic resonance focused surgical and therapeutic ultrasound |
| US5656211A (en) | 1989-12-22 | 1997-08-12 | Imarx Pharmaceutical Corp. | Apparatus and method for making gas-filled vesicles of optimal size |
| US6146657A (en) | 1989-12-22 | 2000-11-14 | Imarx Pharmaceutical Corp. | Gas-filled lipid spheres 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 |
| US6001335A (en) | 1989-12-22 | 1999-12-14 | Imarx Pharmaceutical Corp. | Contrasting agents for ultrasonic imaging and methods for preparing the same |
| US5922304A (en) | 1989-12-22 | 1999-07-13 | Imarx Pharmaceutical Corp. | Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents |
| US5585112A (en) | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
| US6551576B1 (en) | 1989-12-22 | 2003-04-22 | Bristol-Myers Squibb Medical Imaging, Inc. | Container with multi-phase composition for use in diagnostic and therapeutic applications |
| 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 |
| DE4004430A1 (de) * | 1990-02-09 | 1991-08-14 | Schering Ag | Aus polyaldehyden aufgebaute kontrastmittel |
| GB2256183B (en) * | 1990-02-20 | 1994-03-09 | Delta Biotechnology Ltd | Double emulsion technique producing diagnostic aid microcapsules for pharmaceutical use |
| GB9003821D0 (en) * | 1990-02-20 | 1990-04-18 | Danbiosyst Uk | Diagnostic aid |
| US5578292A (en) | 1991-11-20 | 1996-11-26 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| USRE39146E1 (en) | 1990-04-02 | 2006-06-27 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| IN172208B (zh) * | 1990-04-02 | 1993-05-01 | Sint Sa | |
| US5445813A (en) * | 1992-11-02 | 1995-08-29 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
| US5137928A (en) * | 1990-04-26 | 1992-08-11 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
| US5190982A (en) * | 1990-04-26 | 1993-03-02 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
| US5205287A (en) * | 1990-04-26 | 1993-04-27 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
| US5370901A (en) | 1991-02-15 | 1994-12-06 | Bracco International B.V. | Compositions for increasing the image contrast in diagnostic investigations of the digestive tract of patients |
| DE69215722T3 (de) | 1991-03-22 | 2001-03-08 | Katsuro Tachibana | Verstärker zur Ultraschalltherapie von Erkrankungen sowie diesen enthaltende flüssige Arzneimittelzusammensetzungen |
| GB9106673D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
| US5874062A (en) | 1991-04-05 | 1999-02-23 | Imarx Pharmaceutical Corp. | Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents |
| US5205290A (en) | 1991-04-05 | 1993-04-27 | Unger Evan C | Low density microspheres and their use as contrast agents for computed tomography |
| GB9107628D0 (en) * | 1991-04-10 | 1991-05-29 | Moonbrook Limited | Preparation of diagnostic agents |
| US5993805A (en) * | 1991-04-10 | 1999-11-30 | Quadrant Healthcare (Uk) Limited | Spray-dried microparticles and their use as therapeutic vehicles |
| EP0514790A2 (de) * | 1991-05-24 | 1992-11-25 | Hoechst Aktiengesellschaft | Polykondensate, die Weinsäurederivate enthalten, Verfahren zu ihrer Herstellung und Verwendung derselben |
| WO1992021382A1 (en) * | 1991-06-03 | 1992-12-10 | Holmes, Michael, John | Improvements in or relating to contrast agents |
| GB9116610D0 (en) * | 1991-08-01 | 1991-09-18 | Danbiosyst Uk | Preparation of microparticles |
| NZ244147A (en) * | 1991-09-03 | 1994-09-27 | Hoechst Ag | Echogenic particles which comprise a gas and at least one shaping substance, and their use as diagnostic agents |
| MX9205298A (es) | 1991-09-17 | 1993-05-01 | Steven Carl Quay | Medios gaseosos de contraste de ultrasonido y metodo para seleccionar gases para usarse como medios de contraste de ultrasonido |
| US6723303B1 (en) | 1991-09-17 | 2004-04-20 | Amersham Health, As | Ultrasound contrast agents including protein stabilized microspheres of perfluoropropane, perfluorobutane or perfluoropentane |
| US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
| ES2145011T5 (es) * | 1991-09-17 | 2008-02-01 | Ge Healthcare As | Medios de contraste gaseoso para ecografias. |
| IL104084A (en) * | 1992-01-24 | 1996-09-12 | Bracco Int Bv | Sustainable aqueous suspensions of pressure-resistant and gas-filled blisters, their preparation, and contrast agents containing them |
| GB9204918D0 (en) | 1992-03-06 | 1992-04-22 | Nycomed As | Chemical compounds |
| DE4232755A1 (de) * | 1992-09-26 | 1994-03-31 | Schering Ag | Mikropartikelpräparationen aus biologisch abbaubaren Mischpolymeren |
| US6383470B1 (en) | 1992-09-26 | 2002-05-07 | Thomas Fritzsch | Microparticle preparations made of biodegradable copolymers |
| GB9221329D0 (en) * | 1992-10-10 | 1992-11-25 | Delta Biotechnology Ltd | Preparation of further diagnostic agents |
| US5558855A (en) * | 1993-01-25 | 1996-09-24 | Sonus Pharmaceuticals | Phase shift colloids as ultrasound contrast agents |
| IL108416A (en) | 1993-01-25 | 1998-10-30 | Sonus Pharma Inc | Colloids with phase difference as contrast ultrasound agents |
| US5716597A (en) * | 1993-06-04 | 1998-02-10 | Molecular Biosystems, Inc. | Emulsions as contrast agents and method of use |
| DE69434119T3 (de) * | 1993-07-30 | 2011-05-05 | Imcor Pharmaceutical Co., San Diego | Stabilisierte mikrogasbläschen-zusammensetzungen für echographie |
| US5798091A (en) | 1993-07-30 | 1998-08-25 | Alliance Pharmaceutical Corp. | Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement |
| DE59409568D1 (de) * | 1993-09-09 | 2000-11-30 | Schering Ag | Wirkstoffe und gas enthaltende mikropartikel |
| AU679295B2 (en) | 1993-12-15 | 1997-06-26 | Bracco Suisse S.A. | Gas mixtures useful as ultrasound contrast media |
| DE4406474A1 (de) * | 1994-02-23 | 1995-08-24 | Schering Ag | Gas enthaltende Mikropartikel, diese enthaltende Mittel, deren Verwendung in der Ultraschalldiagnostik, sowie Verfahren zur Herstellung der Partikel und Mittel |
| AU2432795A (en) * | 1994-05-03 | 1995-11-29 | Molecular Biosystems, Inc. | Composition for ultrasonically quantitating myocardial perfusion |
| US5730955A (en) * | 1994-08-02 | 1998-03-24 | Molecular Biosystems, Inc. | Process for making gas-filled microspheres containing a liquid hydrophobic barrier |
| US5965109A (en) * | 1994-08-02 | 1999-10-12 | Molecular Biosystems, Inc. | Process for making insoluble gas-filled microspheres containing a liquid hydrophobic barrier |
| US5562893A (en) * | 1994-08-02 | 1996-10-08 | Molecular Biosystems, Inc. | Gas-filled microspheres with fluorine-containing shells |
| US5540909A (en) * | 1994-09-28 | 1996-07-30 | Alliance Pharmaceutical Corp. | Harmonic ultrasound imaging with microbubbles |
| GB9423419D0 (en) | 1994-11-19 | 1995-01-11 | Andaris Ltd | Preparation of hollow microcapsules |
| US5830430A (en) | 1995-02-21 | 1998-11-03 | Imarx Pharmaceutical Corp. | Cationic lipids and the use thereof |
| DE19508049C2 (de) * | 1995-02-23 | 1997-02-06 | Schering Ag | Verwendung von Methylenmalondiesterderivaten zur Herstellung von gasenthaltenden Mikropartikeln |
| DE19510690A1 (de) * | 1995-03-14 | 1996-09-19 | Schering Ag | Polymere Nano- und/oder Mikropartikel, Verfahren zu deren Herstellung, sowie Verwendung in medizinischen Diagnostik und Therapie |
| US5759539A (en) * | 1995-06-06 | 1998-06-02 | Georgia Research Foundation, Inc. | Method for rapid enzymatic alcohol removal |
| US5997898A (en) | 1995-06-06 | 1999-12-07 | Imarx Pharmaceutical Corp. | Stabilized compositions of fluorinated amphiphiles for methods of therapeutic delivery |
| US6231834B1 (en) | 1995-06-07 | 2001-05-15 | Imarx Pharmaceutical Corp. | Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same |
| US6033645A (en) | 1996-06-19 | 2000-03-07 | Unger; Evan C. | Methods for diagnostic imaging by regulating the administration rate of a contrast agent |
| US6521211B1 (en) | 1995-06-07 | 2003-02-18 | Bristol-Myers Squibb Medical Imaging, Inc. | Methods of imaging and treatment with targeted compositions |
| US5804162A (en) * | 1995-06-07 | 1998-09-08 | Alliance Pharmaceutical Corp. | Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients |
| US6139819A (en) | 1995-06-07 | 2000-10-31 | Imarx Pharmaceutical Corp. | Targeted contrast agents for diagnostic and therapeutic use |
| US5820850A (en) * | 1995-06-07 | 1998-10-13 | Molecular Biosystems, Inc. | Gas-filled amino acid block co-polymer microspheres useful as ultrasound contrast agents |
| DE19543077C2 (de) * | 1995-11-13 | 1997-10-16 | Schering Ag | Verwendung von gashaltigen Metallkomplexen als Ultraschallkontrastmittel |
| PT904113E (pt) * | 1996-03-05 | 2004-09-30 | Acusphere Inc | Gases fluorados microencapsulados para utilizacao como agentes de aquisicao de imagem |
| US5611344A (en) * | 1996-03-05 | 1997-03-18 | Acusphere, Inc. | Microencapsulated fluorinated gases for use as imaging agents |
| WO1997040679A1 (en) | 1996-05-01 | 1997-11-06 | Imarx Pharmaceutical Corp. | Methods for delivering compounds into a cell |
| US5837221A (en) * | 1996-07-29 | 1998-11-17 | Acusphere, Inc. | Polymer-lipid microencapsulated gases for use as imaging agents |
| US6414139B1 (en) | 1996-09-03 | 2002-07-02 | Imarx Therapeutics, Inc. | Silicon amphiphilic compounds and the use thereof |
| US6017310A (en) * | 1996-09-07 | 2000-01-25 | Andaris Limited | Use of hollow microcapsules |
| US5846517A (en) | 1996-09-11 | 1998-12-08 | Imarx Pharmaceutical Corp. | Methods for diagnostic imaging using a renal contrast agent and a vasodilator |
| CA2263568C (en) | 1996-09-11 | 2008-12-02 | Imarx Pharmaceutical Corp. | Methods for diagnostic imaging using a contrast agent and a renal vasodilator |
| US6068600A (en) * | 1996-12-06 | 2000-05-30 | Quadrant Healthcare (Uk) Limited | Use of hollow microcapsules |
| GB9701274D0 (en) | 1997-01-22 | 1997-03-12 | Andaris Ltd | Ultrasound contrast imaging |
| US6143276A (en) | 1997-03-21 | 2000-11-07 | Imarx Pharmaceutical Corp. | Methods for delivering bioactive agents to regions of elevated temperatures |
| US6537246B1 (en) | 1997-06-18 | 2003-03-25 | Imarx Therapeutics, Inc. | Oxygen delivery agents and uses for the same |
| US6090800A (en) | 1997-05-06 | 2000-07-18 | Imarx Pharmaceutical Corp. | Lipid soluble steroid prodrugs |
| EP0979071B1 (en) * | 1997-04-30 | 2007-11-07 | Point Biomedical Corporation | Microparticles useful as ultrasonic contrast agents and for delivery of drugs into the bloodstream |
| US6416740B1 (en) | 1997-05-13 | 2002-07-09 | Bristol-Myers Squibb Medical Imaging, Inc. | Acoustically active drug delivery systems |
| US6548047B1 (en) | 1997-09-15 | 2003-04-15 | Bristol-Myers Squibb Medical Imaging, Inc. | Thermal preactivation of gaseous precursor filled compositions |
| US7637948B2 (en) | 1997-10-10 | 2009-12-29 | Senorx, Inc. | Tissue marking implant |
| US8668737B2 (en) | 1997-10-10 | 2014-03-11 | Senorx, Inc. | Tissue marking implant |
| US6123923A (en) | 1997-12-18 | 2000-09-26 | Imarx Pharmaceutical Corp. | Optoacoustic contrast agents and methods for their use |
| US20010003580A1 (en) | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
| GB9800813D0 (en) | 1998-01-16 | 1998-03-11 | Andaris Ltd | Improved ultrasound contrast imaging method and apparatus |
| DE19813174A1 (de) * | 1998-03-25 | 1999-05-27 | Schering Ag | Mikropartikel aus Polymeren und mindestens einer gerüstbildenden Komponente und ihre Herstellung und Verwendung in der Ultraschalldiagnostik und zur ultraschallinduzierten Wirkstofffreisetzung |
| DE19839216C1 (de) * | 1998-08-28 | 2000-01-20 | Aventis Res & Tech Gmbh & Co | Verfahren zur Herstellung von sphärischen Mikropartikeln, die ganz oder teilweise aus mindestens einem wasserunlöslichen Verzweigungen enthaltenden Polyglucan bestehen, sowie mit diesem Verfahren erhältliche Mikropartikel und die Verwendung |
| US8361082B2 (en) | 1999-02-02 | 2013-01-29 | Senorx, Inc. | Marker delivery device with releasable plug |
| US7651505B2 (en) | 2002-06-17 | 2010-01-26 | Senorx, Inc. | Plugged tip delivery for marker placement |
| US7983734B2 (en) | 2003-05-23 | 2011-07-19 | Senorx, Inc. | Fibrous marker and intracorporeal delivery thereof |
| US6862470B2 (en) | 1999-02-02 | 2005-03-01 | Senorx, Inc. | Cavity-filling biopsy site markers |
| US20090030309A1 (en) * | 2007-07-26 | 2009-01-29 | Senorx, Inc. | Deployment of polysaccharide markers |
| US8498693B2 (en) | 1999-02-02 | 2013-07-30 | Senorx, Inc. | Intracorporeal marker and marker delivery device |
| US6725083B1 (en) | 1999-02-02 | 2004-04-20 | Senorx, Inc. | Tissue site markers for in VIVO imaging |
| US9820824B2 (en) | 1999-02-02 | 2017-11-21 | Senorx, Inc. | Deployment of polysaccharide markers for treating a site within a patent |
| GB9912356D0 (en) | 1999-05-26 | 1999-07-28 | Btg Int Ltd | Generation of microfoam |
| DE19925311B4 (de) * | 1999-05-27 | 2004-06-09 | Schering Ag | Mehrstufen-Verfahren zur Herstellung von gasgefüllten Mikrokapseln |
| US6575991B1 (en) | 1999-06-17 | 2003-06-10 | Inrad, Inc. | Apparatus for the percutaneous marking of a lesion |
| EP1202671A4 (en) | 1999-08-13 | 2004-11-10 | Point Biomedical Corp | MICROPARTICLES USEFUL AS ULTRASONIC CONTRAST AGENTS FOR THE LYMPHATIC SYSTEM |
| WO2001012069A1 (en) | 1999-08-13 | 2001-02-22 | Point Biomedical Corporation | Hollow microspheres with controlled fragility for medical use |
| CA2659518A1 (en) | 2000-11-20 | 2002-05-30 | Senorx, Inc. | Tissue site markers for in vivo imaging |
| US8512680B2 (en) | 2001-08-08 | 2013-08-20 | Btg International Ltd. | Injectables in foam, new pharmaceutical applications |
| AU2002359576A1 (en) | 2001-12-03 | 2003-06-17 | Ekos Corporation | Catheter with multiple ultrasound radiating members |
| US20060036158A1 (en) | 2003-11-17 | 2006-02-16 | Inrad, Inc. | Self-contained, self-piercing, side-expelling marking apparatus |
| DK1565563T3 (da) * | 2002-11-22 | 2013-01-21 | Basf Se | Enzymatisk syntese af polyolacrylater |
| US20040185108A1 (en) * | 2003-03-18 | 2004-09-23 | Short Robert E. | Method of preparing gas-filled polymer matrix microparticles useful for delivering drug |
| US7877133B2 (en) | 2003-05-23 | 2011-01-25 | Senorx, Inc. | Marker or filler forming fluid |
| CA2543296A1 (en) | 2003-10-31 | 2005-05-12 | Point Biomedical Corporation | Reconstitutable microsphere compositions useful as ultrasonic contrast agents |
| ES2339117T5 (es) | 2003-11-17 | 2019-04-10 | Btg Int Ltd | Procedimientos de preparación de una espuma que comprende un agente esclerosante |
| US20050273002A1 (en) | 2004-06-04 | 2005-12-08 | Goosen Ryan L | Multi-mode imaging marker |
| US8048439B2 (en) | 2003-11-17 | 2011-11-01 | Btg International Ltd. | Therapeutic foam |
| US7025726B2 (en) | 2004-01-22 | 2006-04-11 | The Regents Of The University Of Nebraska | Detection of endothelial dysfunction by ultrasonic imaging |
| ITMI20041056A1 (it) * | 2004-05-26 | 2004-08-26 | Garrido Antonio Luis Cabrera | Uso in campo medico diagnostico e flebo logico di una kiscela di gas sterili e fisiologicamente accettabili |
| US8012457B2 (en) | 2004-06-04 | 2011-09-06 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
| JP2008527119A (ja) | 2005-01-13 | 2008-07-24 | シンベンション アーゲー | 炭素ナノ粒子を含有する複合材料 |
| US10357328B2 (en) | 2005-04-20 | 2019-07-23 | Bard Peripheral Vascular, Inc. and Bard Shannon Limited | Marking device with retractable cannula |
| GB0509824D0 (en) | 2005-05-13 | 2005-06-22 | Btg Int Ltd | Therapeutic foam |
| WO2007004026A1 (en) * | 2005-06-30 | 2007-01-11 | Ge Healthcare Limited | Evaluating cardiac function with dynamic imaging techniques and contrast media |
| CN100484479C (zh) * | 2005-08-26 | 2009-05-06 | 深圳迈瑞生物医疗电子股份有限公司 | 超声图像增强与斑点抑制方法 |
| US9011473B2 (en) | 2005-09-07 | 2015-04-21 | Ulthera, Inc. | Dissection handpiece and method for reducing the appearance of cellulite |
| US9358033B2 (en) | 2005-09-07 | 2016-06-07 | Ulthera, Inc. | Fluid-jet dissection system and method for reducing the appearance of cellulite |
| US10548659B2 (en) | 2006-01-17 | 2020-02-04 | Ulthera, Inc. | High pressure pre-burst for improved fluid delivery |
| US7967763B2 (en) | 2005-09-07 | 2011-06-28 | Cabochon Aesthetics, Inc. | Method for treating subcutaneous tissues |
| US8518069B2 (en) | 2005-09-07 | 2013-08-27 | Cabochon Aesthetics, Inc. | Dissection handpiece and method for reducing the appearance of cellulite |
| US9486274B2 (en) | 2005-09-07 | 2016-11-08 | Ulthera, Inc. | Dissection handpiece and method for reducing the appearance of cellulite |
| US8052658B2 (en) | 2005-10-07 | 2011-11-08 | Bard Peripheral Vascular, Inc. | Drug-eluting tissue marker |
| US7885793B2 (en) | 2007-05-22 | 2011-02-08 | International Business Machines Corporation | Method and system for developing a conceptual model to facilitate generating a business-aligned information technology solution |
| US9248317B2 (en) | 2005-12-02 | 2016-02-02 | Ulthera, Inc. | Devices and methods for selectively lysing cells |
| US20080230001A1 (en) * | 2006-02-23 | 2008-09-25 | Meadwestvaco Corporation | Method for treating a substrate |
| WO2007127176A2 (en) | 2006-04-24 | 2007-11-08 | Ekos Corporation | Ultrasound therapy system |
| US8064987B2 (en) | 2006-10-23 | 2011-11-22 | C. R. Bard, Inc. | Breast marker |
| EP3542748B1 (en) | 2006-12-12 | 2023-08-16 | C. R. Bard, Inc. | Multiple imaging mode tissue marker |
| ES2432572T3 (es) | 2006-12-18 | 2013-12-04 | C.R. Bard, Inc. | Marcador de biopsia con propiedades de obtención de imágenes generadas in situ |
| US10182833B2 (en) | 2007-01-08 | 2019-01-22 | Ekos Corporation | Power parameters for ultrasonic catheter |
| US9044568B2 (en) | 2007-06-22 | 2015-06-02 | Ekos Corporation | Method and apparatus for treatment of intracranial hemorrhages |
| US8439940B2 (en) | 2010-12-22 | 2013-05-14 | Cabochon Aesthetics, Inc. | Dissection handpiece with aspiration means for reducing the appearance of cellulite |
| US8311610B2 (en) | 2008-01-31 | 2012-11-13 | C. R. Bard, Inc. | Biopsy tissue marker |
| US8822584B2 (en) | 2008-05-06 | 2014-09-02 | Metabolix, Inc. | Biodegradable polyester blends |
| US9327061B2 (en) | 2008-09-23 | 2016-05-03 | Senorx, Inc. | Porous bioabsorbable implant |
| US8670818B2 (en) | 2008-12-30 | 2014-03-11 | C. R. Bard, Inc. | Marker delivery device for tissue marker placement |
| US9358064B2 (en) | 2009-08-07 | 2016-06-07 | Ulthera, Inc. | Handpiece and methods for performing subcutaneous surgery |
| US11096708B2 (en) | 2009-08-07 | 2021-08-24 | Ulthera, Inc. | Devices and methods for performing subcutaneous surgery |
| WO2012136813A2 (en) | 2011-04-07 | 2012-10-11 | Universitetet I Oslo | Agents for medical radar diagnosis |
| CN109054254B (zh) | 2012-08-17 | 2021-02-02 | Cj第一制糖株式会社 | 用于聚合物共混物的生物基橡胶改性剂 |
| US10669417B2 (en) | 2013-05-30 | 2020-06-02 | Cj Cheiljedang Corporation | Recyclate blends |
| USD715442S1 (en) | 2013-09-24 | 2014-10-14 | C. R. Bard, Inc. | Tissue marker for intracorporeal site identification |
| USD716450S1 (en) | 2013-09-24 | 2014-10-28 | C. R. Bard, Inc. | Tissue marker for intracorporeal site identification |
| USD716451S1 (en) | 2013-09-24 | 2014-10-28 | C. R. Bard, Inc. | Tissue marker for intracorporeal site identification |
| USD715942S1 (en) | 2013-09-24 | 2014-10-21 | C. R. Bard, Inc. | Tissue marker for intracorporeal site identification |
| WO2015149029A1 (en) | 2014-03-27 | 2015-10-01 | Metabolix, Inc. | Highly filled polymer systems |
| EP3307388B1 (en) | 2015-06-10 | 2022-06-22 | Ekos Corporation | Ultrasound catheter |
Family Cites Families (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3429827A (en) | 1962-11-23 | 1969-02-25 | Moore Business Forms Inc | Method of encapsulation |
| US4572869A (en) | 1967-04-20 | 1986-02-25 | Ppg Industries, Inc. | Microcapsular opacifiers and method for their production |
| US4173488A (en) | 1968-12-23 | 1979-11-06 | Champion International Corporation | Oil-in-water emulsions containing hydropholeic starch |
| US4069306A (en) | 1974-03-14 | 1978-01-17 | Pharmacia Aktiebolag | X-ray contrast preparation containing a hydrophilic polymer containing amino groups |
| US4096238A (en) * | 1974-12-23 | 1978-06-20 | Alza Corporation | Method for administering drug to the gastrointestinal tract |
| US4089800A (en) | 1975-04-04 | 1978-05-16 | Ppg Industries, Inc. | Method of preparing microcapsules |
| US4177177A (en) | 1976-03-26 | 1979-12-04 | El Aasser Mohamed S | Polymer emulsification process |
| US4186131A (en) * | 1977-04-21 | 1980-01-29 | Mead Johnson & Company | Phenyltetrazolyloxy propanolamines |
| US4370160A (en) * | 1978-06-27 | 1983-01-25 | Dow Corning Corporation | Process for preparing silicone microparticles |
| US4276885A (en) * | 1979-05-04 | 1981-07-07 | Rasor Associates, Inc | Ultrasonic image enhancement |
| US4265251A (en) | 1979-06-28 | 1981-05-05 | Rasor Associates, Inc. | Method of determining pressure within liquid containing vessel |
| AU545866B2 (en) | 1980-11-17 | 1985-08-01 | Schering Aktiengesellschaft | Microbubble precursors and methods for their production and use |
| US4657756A (en) | 1980-11-17 | 1987-04-14 | Schering Aktiengesellschaft | Microbubble precursors and apparatus for their production and use |
| US4681119A (en) | 1980-11-17 | 1987-07-21 | Schering Aktiengesellschaft | Method of production and use of microbubble precursors |
| US4442843A (en) | 1980-11-17 | 1984-04-17 | Schering, Ag | Microbubble precursors and methods for their production and use |
| US4365251A (en) | 1980-12-04 | 1982-12-21 | Westinghouse Electric Corp. | Electrically driven meter totalizing device |
| HU180183B (en) * | 1980-12-19 | 1983-02-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing stable suppository compositions containing volatile and/or labile active substances |
| FR2504408B1 (fr) * | 1981-04-24 | 1986-02-14 | Couvreur Patrick | Procede de preparation de particules submicroscopiques, particules ainsi obtenues et compositions pharmaceutiques les contenant |
| HU183430B (en) * | 1981-05-12 | 1984-05-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing cyclodextrine inclusion complexes of n-bracket-1-phenylethyl-bracket closed-3,3-diphenylpropylamine or n-bracket-1-phenylethyl-bracket closed-3,3-diphenylpropylamine-hydrochloride |
| IL63220A (en) | 1981-07-01 | 1985-09-29 | Yeda Res & Dev | Process for production of polyacrolein microspheres |
| DE3141641A1 (de) | 1981-10-16 | 1983-04-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Ultraschall-kontrastmittel und dessen herstellung |
| US4637905A (en) | 1982-03-04 | 1987-01-20 | Batelle Development Corporation | Process of preparing microcapsules of lactides or lactide copolymers with glycolides and/or ε-caprolactones |
| US4718433A (en) | 1983-01-27 | 1988-01-12 | Feinstein Steven B | Contrast agents for ultrasonic imaging |
| DE3313946A1 (de) | 1983-04-15 | 1984-10-18 | Schering AG, 1000 Berlin und 4709 Bergkamen | Mikropartikel und gasblaeschen enthaltende ultraschall-kontrastmittel |
| US5141738A (en) | 1983-04-15 | 1992-08-25 | Schering Aktiengesellschaft | Ultrasonic contrast medium comprising gas bubbles and solid lipophilic surfactant-containing microparticles and use thereof |
| DE3313947A1 (de) | 1983-04-15 | 1984-10-18 | Schering AG, 1000 Berlin und 4709 Bergkamen | Mikropartikel und gasblaeschen enthaltende ultraschall-kontrastmittel |
| US4900540A (en) | 1983-06-20 | 1990-02-13 | Trustees Of The University Of Massachusetts | Lipisomes containing gas for ultrasound detection |
| DE3341001A1 (de) * | 1983-11-12 | 1985-05-23 | Krause, Hans Jürgen | Nanopartikel aus bioabbaubarem, synthetischem material, verfahren zu deren herstellung und ihre anwendung |
| US5618514A (en) * | 1983-12-21 | 1997-04-08 | Nycomed Imaging As | Diagnostic and contrast agent |
| SE463651B (sv) * | 1983-12-21 | 1991-01-07 | Nycomed As | Diagnostikum och kontrastmedel |
| SU1357410A1 (ru) * | 1985-01-24 | 1987-12-07 | Предприятие П/Я Р-6710 | Способ получени соединений включени @ -циклодекстрина и инертных газов |
| US4886068A (en) | 1985-07-29 | 1989-12-12 | Kabushiki Kaisha Toshiba | Ultrasonic coupling agent |
| DE3529195A1 (de) * | 1985-08-14 | 1987-02-26 | Max Planck Gesellschaft | Kontrastmittel fuer ultraschalluntersuchungen und verfahren zu seiner herstellung |
| CS255758B1 (en) * | 1985-12-11 | 1988-03-15 | Frantisek Rypacek | Preparat for the diagnostic of transportion function of oviduct and process for preparing thereof |
| DE3785365T2 (de) * | 1986-01-08 | 1993-09-16 | Kao Corp | Badezusatz. |
| US4741872A (en) | 1986-05-16 | 1988-05-03 | The University Of Kentucky Research Foundation | Preparation of biodegradable microspheres useful as carriers for macromolecules |
| FR2604903B1 (fr) | 1986-10-08 | 1989-01-13 | Sopar Sa Nv | Agents therapeutiques sous forme de particules submicroscopiques contre des parasitoses et compositions pharmaceutiques les contenant |
| DE3637926C1 (de) | 1986-11-05 | 1987-11-26 | Schering Ag | Ultraschall-Manometrieverfahren in einer Fluessigkeit mittels Mikroblaeschen |
| US5174930A (en) * | 1986-12-31 | 1992-12-29 | Centre National De La Recherche Scientifique (Cnrs) | Process for the preparation of dispersible colloidal systems of amphiphilic lipids in the form of oligolamellar liposomes of submicron dimensions |
| FR2608942B1 (fr) | 1986-12-31 | 1991-01-11 | Centre Nat Rech Scient | Procede de preparation de systemes colloidaux dispersibles d'une substance, sous forme de nanocapsules |
| US4844882A (en) * | 1987-12-29 | 1989-07-04 | Molecular Biosystems, Inc. | Concentrated stabilized microbubble-type ultrasonic imaging agent |
| US5425366A (en) | 1988-02-05 | 1995-06-20 | Schering Aktiengesellschaft | Ultrasonic contrast agents for color Doppler imaging |
| DE8900069U1 (zh) * | 1989-01-04 | 1989-03-09 | Schneider, Elke, 4052 Korschenbroich, De | |
| US5205287A (en) | 1990-04-26 | 1993-04-27 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
| US5236693A (en) * | 1990-11-14 | 1993-08-17 | Brigham And Women's Hospital | Medical ultrasound contrast agent and method of using same |
| US5107842A (en) | 1991-02-22 | 1992-04-28 | Molecular Biosystems, Inc. | Method of ultrasound imaging of the gastrointestinal tract |
| US5147631A (en) | 1991-04-30 | 1992-09-15 | Du Pont Merck Pharmaceutical Company | Porous inorganic ultrasound contrast agents |
| US5409688A (en) | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
| JPH05262673A (ja) * | 1992-03-19 | 1993-10-12 | Nippon Paint Co Ltd | 超音波診断用造影剤 |
-
1989
- 1989-02-01 IE IE34389A patent/IE66912B1/en not_active IP Right Cessation
- 1989-02-01 ES ES89901933T patent/ES2068917T3/es not_active Expired - Lifetime
- 1989-02-01 EP EP89901933A patent/EP0398935B1/de not_active Revoked
- 1989-02-01 AU AU30351/89A patent/AU635200B2/en not_active Ceased
- 1989-02-01 DE DE58908194T patent/DE58908194D1/de not_active Revoked
- 1989-02-01 KR KR1019890701826A patent/KR0133132B1/ko not_active IP Right Cessation
- 1989-02-01 JP JP1501696A patent/JP2907911B2/ja not_active Expired - Lifetime
- 1989-02-01 EP EP93112378A patent/EP0586875A1/de not_active Withdrawn
- 1989-02-01 AT AT89901933T patent/ATE109663T1/de not_active IP Right Cessation
- 1989-02-01 HU HU055/89A patent/HU221485B/hu not_active IP Right Cessation
- 1989-02-01 WO PCT/DE1989/000069 patent/WO1989006978A1/de not_active Application Discontinuation
- 1989-02-01 EP EP89730021A patent/EP0327490A1/de active Pending
- 1989-02-03 IL IL89175A patent/IL89175A/xx not_active IP Right Cessation
- 1989-02-03 CA CA000590059A patent/CA1336164C/en not_active Expired - Fee Related
- 1989-02-03 PT PT89635A patent/PT89635B/pt not_active IP Right Cessation
- 1989-02-03 IE IE940809A patent/IE940809L/xx unknown
- 1989-02-04 CN CN89100726A patent/CN1033840C/zh not_active Expired - Fee Related
- 1989-02-04 MY MYPI89000146A patent/MY105856A/en unknown
- 1989-02-07 NZ NZ227869A patent/NZ227869A/xx unknown
-
1990
- 1990-06-11 US US07/536,373 patent/US6264959B1/en not_active Expired - Fee Related
- 1990-08-03 FI FI903865A patent/FI99086C/fi not_active IP Right Cessation
- 1990-08-03 DK DK199001864A patent/DK175832B1/da not_active IP Right Cessation
- 1990-08-06 NO NO903443A patent/NO301260B1/no not_active IP Right Cessation
-
1995
- 1995-06-07 US US08/477,642 patent/US6071496A/en not_active Expired - Fee Related
- 1995-06-07 US US08/474,468 patent/US6177062B1/en not_active Expired - Lifetime
- 1995-11-24 JP JP7306254A patent/JP3027326B2/ja not_active Expired - Lifetime
-
1997
- 1997-02-17 NO NO970732A patent/NO304412B1/no not_active IP Right Cessation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1064851C (zh) * | 1992-06-13 | 2001-04-25 | 舍林股份公司 | 微粒，其制造方法以及在诊断中的应用 |
| CN1068230C (zh) * | 1993-01-25 | 2001-07-11 | 索纳斯药品有限公司 | 用作超声造影剂的相转变胶体 |
| CN1066963C (zh) * | 1993-03-16 | 2001-06-13 | 奈科姆成像有限公司 | 造影剂及其改进 |
| CN104994800A (zh) * | 2013-03-29 | 2015-10-21 | 奥林巴斯株式会社 | 超声波治疗装置 |
| CN104994800B (zh) * | 2013-03-29 | 2019-01-08 | 奥林巴斯株式会社 | 超声波治疗装置 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1033840C (zh) | 制备用于超声造影的微粒和超声波造影剂的方法 | |
| CN1080559C (zh) | 制备持续释放制剂的方法 | |
| CN1146408C (zh) | 聚(丙二酸亚甲基酯)微球体、其制备方法及其药物组合物 | |
| CN1083849C (zh) | 制备多糖凝胶组合物的方法、由该方法得到的产品及其用途 | |
| RU2103994C1 (ru) | Композиция в форме микросфер для пролонгированного и контролируемого высвобождения пептидного лекарственного вещества | |
| CN1602186A (zh) | 缓释可生物降解微球体及其制备方法 | |
| FR2810885A1 (fr) | Microparticule a liberation soutenue et procede de fabrication | |
| CN1088092A (zh) | 微颗粒制剂及其生产方法 | |
| CN1852687A (zh) | 控释组合物的制备方法 | |
| CN100345535C (zh) | 胰岛素控释制剂及其方法 | |
| JP5946843B2 (ja) | 超音波によりコラーゲンを抽出する方法及びその装置 | |
| CN1194002C (zh) | 短链化多核苷酸及其制备方法 | |
| CN1082924A (zh) | 微粒，其制造方法以及在诊断中的应用 | |
| CN1913875A (zh) | 作为药物载体的具有pH依赖性调节释放性质的阴离子水凝胶基质 | |
| CN1032346A (zh) | 其表面上固定有带可离子化或活性基团的两亲分子的聚合物颗粒，其制备方法及其在生物学上的应用 | |
| CN1254496C (zh) | 制备分枝型聚乙二醇的方法 | |
| CN1058706C (zh) | 前列腺素衍生物 | |
| CN1263736C (zh) | 四水合n－[邻－(对－三甲基乙酰氧基苯磺酰胺基)苯甲酰基]甘氨酸单钠盐的溶液及其药品 | |
| CN1159288C (zh) | 蛋白质修饰剂及其制备方法和用途 | |
| CN1193761C (zh) | 一种糖皮质激素的可控释放体系及其制备方法 | |
| CH672887A5 (zh) | ||
| CN1198735A (zh) | 苯磺酰胺衍生物以及它们的制备和在医领域中的应用 | |
| FR2634121A1 (fr) | Procede de preparation de microparticules de collagene et produits obtenus | |
| JPH09255590A (ja) | 徐放性薬剤 | |
| CN1309554A (zh) | 生物活性组合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
| OR01 | Other related matters | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |