DE3803971C1 - Ultrasound contrast medium - Google Patents
Ultrasound contrast mediumInfo
- Publication number
- DE3803971C1 DE3803971C1 DE3803971A DE3803971A DE3803971C1 DE 3803971 C1 DE3803971 C1 DE 3803971C1 DE 3803971 A DE3803971 A DE 3803971A DE 3803971 A DE3803971 A DE 3803971A DE 3803971 C1 DE3803971 C1 DE 3803971C1
- Authority
- DE
- Germany
- Prior art keywords
- ultrasound contrast
- microparticles
- contrast medium
- methyl
- medium according
- 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.)
- Expired
Links
- 239000002961 echo contrast media Substances 0.000 title claims abstract description 17
- 239000011859 microparticle Substances 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 7
- 239000007789 gas Substances 0.000 claims description 12
- 229920000858 Cyclodextrin Polymers 0.000 claims description 6
- -1 1,1-dichlorethylene 2-methyl-2-butene Isopropyl chloride 2-methyl-1,3-butadiene 2-butyne 2-methyl-1-butene Dibromodifluoromethane Furan 3-methyl-1-butene Isopentane Chemical compound 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 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
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000012736 aqueous medium 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
- 239000008103 glucose Substances 0.000 claims description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 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
- 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
- 239000001273 butane Substances 0.000 claims description 2
- 239000003925 fat Substances 0.000 claims description 2
- 229930182830 galactose Natural products 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 claims description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 239000001294 propane Substances 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class 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 2
- 239000000341 volatile oil Substances 0.000 claims description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 claims 1
- 239000011248 coating agent Substances 0.000 claims 1
- 238000000576 coating method Methods 0.000 claims 1
- 229940097362 cyclodextrins Drugs 0.000 claims 1
- 230000002209 hydrophobic effect Effects 0.000 claims 1
- 229910052743 krypton Inorganic materials 0.000 claims 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 claims 1
- 229910052724 xenon Inorganic materials 0.000 claims 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 claims 1
- 229920000881 Modified starch Polymers 0.000 abstract 1
- 229920002472 Starch Polymers 0.000 abstract 1
- 235000019426 modified starch Nutrition 0.000 abstract 1
- 235000019698 starch Nutrition 0.000 abstract 1
- 239000008107 starch Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 11
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 10
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-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)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 WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical class 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 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 4
- 239000001116 FEMA 4028 Substances 0.000 description 4
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 4
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 4
- 229960004853 betadex Drugs 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 3
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 2
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Natural products O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- PDEXVOWZLSWEJB-UHFFFAOYSA-N krypton xenon Chemical compound [Kr].[Xe] PDEXVOWZLSWEJB-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
Classifications
-
- 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
Description
Die Erfindung betrifft ein Ultraschallkontrastmittel nach dem Oberbegriff des Patentanspruchs 1.The invention relates to an ultrasound contrast agent according to the preamble of claim 1.
Als Kontrastmittel werden in der medizinischen Ultraschalldiagnostik Gas enthaltende oder Gas produzie rende Substanzen verwendet (Roelandt, Contrast Echocardiography, Ultrasound Med Biol 8: 471-492, 1982). Daneben gibt es Ultraschallkontrastmittel in Form von Partikeln (Ophir, Gobuty, Mc Whirt, Maklad, Ultrasonic Backscatter from Contrast-producing Collagen Microspheres, Ultrasonic Imaging 2: 66-67, 1980). Ferner werden (Ophir, Mc Whirt, Maklad, Aqueous Solutions as Potential Ultrasonic Contrast Agents, Ultrasonic Imaging 1: 265-279, 1979 sowie Tyler, Ophir, Maklad, In-vivo Enhancement of Ultrasonic Image Luminance by Aqueous Solutions with High Speed of Sound, Ultrasonic Imaging 3: 323-329, 1981) oder es werden Lösungen höherer Dichte als Ultraschall-Kontrastmittel eingesetzt. Es ist auch bekannt, Emulsionen als Ultraschall-Kontrastmittel zu verwenden (Mattrey, Andre, Ultrasonic Enhancement of Myocardial Infarction with Perfluorcarbon Compounds in Dogs, Am J Cardiol 54: 206-210, 1984).As a contrast medium in medical Ultrasound diagnostics containing gas or gas produzie substances (Roelandt, Contrast Echocardiography, Ultrasound Med Biol 8: 471-492, 1982). There are also ultrasound contrast agents in the form of Particles (Ophir, Gobuty, Mc Whirt, Maklad, Ultrasonic Backscatter from Contrast-producing collages Microspheres, Ultrasonic Imaging 2: 66-67, 1980). Further (Ophir, Mc Whirt, Maklad, Aqueous Solutions as Potential Ultrasonic Contrast Agents, Ultrasonic Imaging 1: 265-279, 1979 and Tyler, Ophir, Maklad, in vivo Enhancement of Ultrasonic Image Luminance by Aqueous Solutions with High Speed of Sound, Ultrasonic Imaging 3: 323-329, 1981) or higher density solutions used as an ultrasound contrast medium. It is also known to emulsions as ultrasound contrast agents use (Mattrey, Andre, Ultrasonic Enhancement of Myocardial Infarction with Perfluorcarbon Compounds in Dogs, Am J Cardiol 54: 206-210, 1984).
Es hat sich gezeigt, daß die gasfreien Kontrastmittel insgesamt nur eine geringe Effizienz besitzen. Die gas haltigen Zubereitungen haben den Nachteil einer nur ge ringen in-vivo Stabilität. Darüber hinaus ist die Größe der Gasblasen zu meist nicht standardisierbar. Aus reichende Kontrasteffekte sind im arteriellen Gefäß system nach peripher venöser Injektion in aller Regel nicht möglich.It has been shown that the gas-free contrast agents overall have low efficiency. The gas Prepared preparations have the disadvantage of only one wrestle in vivo stability. In addition, the size the gas bubbles are mostly not standardized. Off sufficient contrast effects are in the arterial vessel system after peripheral venous injection as a rule not possible.
In den EP A2 1 23 235 und 01 22 624 werden Gasbläschen enthaltende Ultraschall-Kontrastmittel beschrieben, die die Lungenkapillaren passieren können und damit den ge wünschten Kontrasteffekt bewirken.EP A2 1 23 235 and 01 22 624 describe gas bubbles containing ultrasound contrast agents described that can pass through the lung capillaries and thus the ge desired effect of contrast.
Die EP A2 02 24 934 beschreibt Ultraschall-Kontrast mittel in Form von gasgefüllten Gelantine- oder Albumin hohlkörpern. Nachteilig ist jedoch die Verwendung von körperfremden Eiweißen und das damit verbundene aller gene Risiko sowie die Emboliegefahr. Das sich die dena turierten Proteine im Körper nicht auflösen, sondern langsam abgebaut werden, besteht die Gefahr, daß es zur Verlegung von Arteriolen oder Kapillaren beispielsweise im cerebralen Bereich kommt.EP A2 02 24 934 describes ultrasound contrast medium in the form of gas-filled gelatin or albumin hollow bodies. However, the use of is disadvantageous foreign proteins and all of them risk and the risk of embolism. That dena not dissolve turiated proteins in the body, but are slowly broken down, there is a risk that it will Laying arterioles or capillaries, for example comes in the cerebral area.
Der Erfindung liegt die Aufgabe zugrunde, ein neues für den Menschen gut verträgliches Ultraschallkontrastmittel zur Verfügung zu stellen.The invention has for its object a new for ultrasound contrast medium that is well tolerated by humans to provide.
Diese Aufgabe wird durch Mikropartikel nach dem Pa tentanspruch 1 gelöst.This task is carried out by microparticles according to Pa Claim 1 solved.
Mit besonderem Vorteil enthalten die Mikropartikel eine organische Flüssigkeit oder ein Lösungsmittel mit einem Siedepunkt unter 60°C, insbesondere wenigstens eines der folgenden organischen Flüssigkeiten und/oder Lösungsmittel:The microparticles contain a particularly advantageous one organic liquid or a solvent with a Boiling point below 60 ° C, especially at least one the following organic liquids and / or Solvent:
1,1-Dichlorethylen
2-Methyl-2-Buten
Isopropylchlorid
2-Methyl-1,3-Butadien
2-Butin
2-Methyl-1-Buten
Dibromdifluormethan
Furan
3-Methyl-1-Buten
Isopentan
Diethylether
3,3-Dimethyl-1-Butin
Dimethylaminoaceton
Propylenoxid
N-Ethylmethylamin
Brommethan
N-Ethyldimethylamin
Methylenchlorid1,1-dichlorethylene
2-methyl-2-butene
Isopropyl chloride
2-methyl-1,3-butadiene
2-butyne
2-methyl-1-butene
Dibromodifluoromethane
Furan
3-methyl-1-butene
Isopentane
Diethyl ether
3,3-dimethyl-1-butyne
Dimethylaminoacetone
Propylene oxide
N-ethylmethylamine
Bromomethane
N-ethyldimethylamine
Methylene chloride
Als gasförmige Komponente enthalten die Mikropartikel mindestens ein Gas der folgenden GruppeThe microparticles contain as a gaseous component at least one gas from the following group
Stickstoff
Krypton
Xenon
Sauerstoff
Kohlendioxid
Ethylen
Methan
Ethan
Propan
Butannitrogen
krypton
xenon
oxygen
Carbon dioxide
Ethylene
methane
Ethan
propane
butane
Mit Vorteil können die Mikropartikel auch Substanzen mit niedrigen Dampfdrücken und/oder niedrigen Siedepunkten, insbesondere ätherische Öle enthalten.The microparticles can also advantageously contain substances low vapor pressures and / or low boiling points, in particular contain essential oils.
Besonders vorteilhaft ist es, die Mikropartikel mit einer Hüllsubstanz zu überziehen. Dabei können die Mikropartikel von Ölen, Fetten und/oder oberflächenak tiven Substanzen umhüllt und in wäßrigem Medium emul giert sein.It is particularly advantageous to use the microparticles to coat an enveloping substance. The Microparticles of oils, fats and / or surface ac tive substances enveloped and emulsified in aqueous medium be greedy.
Besonders vorteilhaft ist es, die Mikropartikel mit einer Matrix, insbesondere polymerer Struktur zu um hüllen.It is particularly advantageous to use the microparticles a matrix, in particular a polymeric structure envelop.
Durch Zugabe osmotisch aktiver Substanzen, insbesondere Kochsalz, Galaktose, Glukose, Fruktose kann die physio logische Isotonie eingestellt werden.By adding osmotically active substances, in particular Saline, galactose, glucose, fructose can be the physio logical isotonicity can be set.
100 ml gesättigte β-Cyclodextrin-Lösung (1,8%ig) wird bei 10°C gekühlt und mit 3 ml Isopentan versetzt. Unter ständigem Rühren im Ultraschallbad wird der entstehende schwerlösliche Komplex ausgefällt. Durch Gefriertrocknen und Filtrieren wird der Niederschlag in kristalliner Form erhalten. Isopentangehalt nach GC-Bestimmung: 0,26%.100 ml of saturated β- cyclodextrin solution (1.8%) is cooled at 10 ° C. and 3 ml of isopentane are added. The resulting poorly soluble complex is precipitated with constant stirring in an ultrasonic bath. The precipitate is obtained in crystalline form by freeze-drying and filtering. Isopentane content according to GC determination: 0.26%.
100 ml gesättigte β-Cyclodextrin-Lösung (1,8%ig) wird bei 10°C gekühlt und mit 3 ml 2-Methyl-2-Buten ver setzt. Unter ständigem Rühren im Ultraschallbad wird der entstehende schwerlösliche Komplex ausgefällt. Durch Gefriertrocknen und Filtrieren wird der Niederschlag in kristalliner Form erhalten.100 ml of saturated β- cyclodextrin solution (1.8%) is cooled at 10 ° C. and mixed with 3 ml of 2-methyl-2-butene. The resulting poorly soluble complex is precipitated with constant stirring in an ultrasonic bath. The precipitate is obtained in crystalline form by freeze-drying and filtering.
100 ml gesättigte β-Cyclodextrin-Lösung (1,8%ig) wird bei 10°C gekühlt und mit 3 ml 2-Methyl-1-Buten ver setzt. Unter ständigem Rühren im Ultraschallbad wird der entstehende schwerlösliche Komplex ausgefällt. Durch Gefriergetrocknen und Filtrieren wird der Niederschlag in kristalliner Form erhalten. 2-Methyl-1-Buten-Gehalt nach GC-Bestimmung: 0,82%.100 ml of saturated β- cyclodextrin solution (1.8%) is cooled at 10 ° C. and mixed with 3 ml of 2-methyl-1-butene. The resulting poorly soluble complex is precipitated with constant stirring in an ultrasonic bath. The precipitate is obtained in crystalline form by freeze-drying and filtering. 2-methyl-1-butene content according to GC determination: 0.82%.
100 ml gesättigte β-Cyclodextrin-Lösung (1,8%ig) wird bei 10°C gekühlt und mit 3 ml Isopren versetzt. Unter ständigem Rühren im Ultraschallbad wird der entstehende schwerlösliche Komplex ausgefällt. Durch Gefrierge trocknung und Filtrieren wird der Niederschlag in kristalliner Form erhalten. Isoprengehalt nach GC- Bestimmung: 1,0%.100 ml of saturated β- cyclodextrin solution (1.8%) is cooled at 10 ° C. and mixed with 3 ml of isoprene. The resulting poorly soluble complex is precipitated with constant stirring in an ultrasonic bath. Freeze drying and filtering give the precipitate in crystalline form. Isoprene content according to GC determination: 1.0%.
100 ml gesättigte β-Cyclodextrin-Lösung (1,8%ig) wird bei 10°C gekühlt und mit 3 ml Isopropylchlorid ver setzt. Unter ständigem Rühren im Ultraschallbad wird der entstehende schwerlösliche Komplex ausgefällt. Durch Gefriertrocknen und Filtrieren wird der Niederschlag in kristalliner Form erhalten. Isopropylchloridgehalt nach GC-Bestimmung: 0,5%.100 ml of saturated β- cyclodextrin solution (1.8%) is cooled at 10 ° C. and mixed with 3 ml of isopropyl chloride. The resulting poorly soluble complex is precipitated with constant stirring in an ultrasonic bath. The precipitate is obtained in crystalline form by freeze-drying and filtering. Isopropyl chloride content according to GC determination: 0.5%.
100 ml gesättigte β-Cyclodextrin-Lösung (1,8%ig) wird bei 10°C gekühlt und mit 20 mg Isopentan versetzt. Unter ständigem Rühren im Ultraschallbad wird der entstehende schwerlösliche Komplex ausgefällt. Durch Gefriertrocknen und Filtrieren wird der Niederschlag in kristalliner Form erhalten. 100 ml of saturated β- cyclodextrin solution (1.8%) is cooled at 10 ° C. and 20 mg of isopentane are added. The resulting poorly soluble complex is precipitated with constant stirring in an ultrasonic bath. The precipitate is obtained in crystalline form by freeze-drying and filtering.
In einem 200 cm3 Autoklaven werden 100 ml gesättigte α- Cyclodextrin-Lösung (ca. 12%ig) unter 7 Atmosphären 7 Tage lang bei Zimmertemperatur inkubiert. Das kristal line Addukt kann abgesaugt, mit kaltem Wasser gewaschen und im Exsikkator über CaCl2 getrocknet werden.In a 200 cm 3 autoclave, 100 ml of saturated α -cyclodextrin solution (approx. 12%) are incubated under 7 atmospheres for 7 days at room temperature. The crystalline line adduct can be filtered off, washed with cold water and dried over CaCl 2 in a desiccator.
In einem 200 cm3 Autoklaven werden 100 ml gesättigte α- Cyclodextrin-Lösung (ca. 12%ig) unter 7 Atmosphären 7 Tage lang bei Zimmertemperatur inkubiert. Das kristalline Addukt kann abgesaugt, mit kaltem Wasser gewaschen und im Exsikkator über CaCl2 getrocknet werden.In a 200 cm 3 autoclave, 100 ml of saturated α -cyclodextrin solution (approx. 12%) are incubated under 7 atmospheres for 7 days at room temperature. The crystalline adduct can be filtered off, washed with cold water and dried over CaCl 2 in a desiccator.
15 ml 20%ige Hydroxypropyl-β-Cyclodextrin-Lösung werden bei 10°C mit 2 ml Isopentan versetzt, im Ultraschallbad 3 min beschallt und danach für 26 Stunden inkubiert. Der entstandene Komplex bleibt in Lösung.15 ml of 20% hydroxypropyl- β- cyclodextrin solution are mixed with 10 ml of isopentane at 10 ° C., sonicated in an ultrasonic bath for 3 minutes and then incubated for 26 hours. The resulting complex remains in solution.
15 ml 20%ige Hydroxypropyl-β-Cyclodextrin-Lösung werden bei 10°C mit 2 ml Isopren versetzt, im Ultraschallbad 3 min beschallt und danach für 26 Stunden inkubiert. Der ent standene Komplex bleibt zum Teil in Lösung und fällt zu einem Teil als weißer Niederschlag aus.15 ml of 20% hydroxypropyl- β- cyclodextrin solution are mixed with 2 ml of isoprene at 10 ° C., sonicated for 3 minutes in an ultrasonic bath and then incubated for 26 hours. The resulting complex remains partly in solution and partly precipitates as a white precipitate.
15 ml 20%ige Hydroxypropyl-β-Cyclodextrin-Lösung wurden bei 10°C mit 2 ml Furan versetzt, im Ultraschallbad 3 min be schallt und danach für 26 Stunden inkubiert. Der ent standene Komplex bleibt zum Teil in Lösung und fällt zu einem Teil als weißer Niederschlag aus.15 ml of 20% hydroxypropyl- β- cyclodextrin solution were mixed with 10 ml of furan at 10 ° C., sonicated for 3 minutes in an ultrasonic bath and then incubated for 26 hours. The resulting complex remains partly in solution and partly precipitates as a white precipitate.
20 ml gesättigte α-Cyclodextrin-Lösung werden mit 1 ml Isopentan versetzt und im Ultraschallbad 3 min beschallt. Der entstehende schwerlösliche Komplex wird durch Filtration gewonnen und über CaCl2 getrocknet.20 ml of saturated α- cyclodextrin solution are mixed with 1 ml of isopentane and sonicated for 3 minutes in an ultrasonic bath. The resulting poorly soluble complex is collected by filtration and dried over CaCl 2 .
20 ml gesättigte α-Cyclodextrin-Lösung werden mit 1 ml Isopren versetzt und im Ultraschallbad 3 min beschallt. Der ent stehende schwerlösliche Komplex wird durch Filtration gewonnen und über CaCl2 getrocknet.20 ml of saturated α- cyclodextrin solution are mixed with 1 ml of isoprene and sonicated in an ultrasound bath for 3 minutes. The resulting sparingly soluble complex is collected by filtration and dried over CaCl 2 .
20 ml gesättigte α-Cyclodextrin-Lösung werden mit 1 ml Furan ver setzt und im Ultraschallbad 3 min beschallt. Der ent stehende schwerlösliche Komplex wird durch Filtration gewonnen und über CaCl2 getrocknet.20 ml of saturated α- cyclodextrin solution are mixed with 1 ml of furan and sonicated for 3 minutes in an ultrasonic bath. The resulting sparingly soluble complex is collected by filtration and dried over CaCl 2 .
Für alle Mittel gilt:The following applies to all means:
Der kristalline Niederschlag wird nach dem Reinigen in einem geeigneten wäßrigen Medium, vorzugsweise physiolo gischer Kochsalz-, Glukose- oder Ringerlösung aufge nommen und ist dann injektionsfertig. Nach der Injektion entstehen Gasblasen geeigneter Größe.The crystalline precipitate is after cleaning in a suitable aqueous medium, preferably physiolo gisch saline, glucose or Ringer solution taken and is then ready for injection. After the injection gas bubbles of a suitable size are formed.
Claims (7)
1,1-Dichlorethylen
2-Methyl-2-Buten
Isopropylchlorid
2-Methyl-1,3-Butadien
2-Butin
2-Methyl-1-Buten
Dibromdifluormethan
Furan
3-Methyl-1-Buten
Isopentan
Diethylether
3,3-Dimethyl-1-Butin
Dimethylaminoaceton
Propylenoxid
N-Ethylmethylamin
Brommethan
N-Ethyldimethylamin
Methylenchlorid 2. Ultrasound contrast medium according to claim 1, characterized in that the microparticles contain at least one of the following organic liquids with a boiling point below 60 ° C:
1,1-dichlorethylene
2-methyl-2-butene
Isopropyl chloride
2-methyl-1,3-butadiene
2-butyne
2-methyl-1-butene
Dibromodifluoromethane
Furan
3-methyl-1-butene
Isopentane
Diethyl ether
3,3-dimethyl-1-butyne
Dimethylaminoacetone
Propylene oxide
N-ethylmethylamine
Bromomethane
N-ethyldimethylamine
Methylene chloride
die Mikropartikel als Gase
Stickstoff,
Krypton,
Xenon,
Sauerstoff,
Kohlendioxid,
Ethylen,
Methan,
Ethan,
Propan oder
Butan
oder deren Gemische enthalten.3. Ultrasound contrast medium according to claim 1, characterized in that
the microparticles as gases
Nitrogen,
Krypton,
Xenon,
Oxygen,
Carbon dioxide,
Ethylene,
Methane,
Ethan,
Propane or
butane
or contain mixtures thereof.
Priority Applications (31)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3803971A DE3803971C2 (en) | 1988-02-05 | 1988-02-05 | Ultrasound contrast media |
EP89730021A EP0327490A1 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic imaging agents, process for their preparation and their diagnostic and therapeutical use |
IE34389A IE66912B1 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic contrast agents process for their preparation and their use as diagnostic and therapeutic agents |
DE58908194T DE58908194D1 (en) | 1988-02-05 | 1989-02-01 | ULTRASONIC CONTRAST AGENTS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS DIAGNOSTICS AND THERAPEUTICS. |
PCT/DE1989/000069 WO1989006978A1 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic contrast agents, process for producing them and their use as diagnostic and therapeutic agents |
KR1019890701826A KR0133132B1 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic contrast agents, process for producing them and their use as diagnostics |
EP89901933A EP0398935B1 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic contrast agents, process for producing them and their use as diagnostic and therapeutic agents |
AT89901933T ATE109663T1 (en) | 1988-02-05 | 1989-02-01 | ULTRASONIC CONTRAST AGENT, PROCESS FOR THEIR PREPARATION AND THEIR USE AS DIAGNOSTICS AND THERAPEUTICS. |
HU9601731A HU9601731D0 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic contrastmaterials, process for producing them and their use as diagnostics and therapeutical materials |
HU055/89A HU221485B (en) | 1988-02-05 | 1989-02-01 | Ultrasound contrast media consisting of microparticles and process for producing the same |
ES89901933T ES2068917T3 (en) | 1988-02-05 | 1989-02-01 | CONTRAST MEANS BY ULTRASOUND, PROCEDURE FOR THEIR OBTAINING AND USE OF THEM AS DIAGNOSTIC AND THERAPEUTIC PRODUCTS. |
AU30351/89A AU635200B2 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic contrast agents, process for producing them and their use as diagnostic and therapeutic agents |
EP93112378A EP0586875A1 (en) | 1988-02-05 | 1989-02-01 | Ultrasonic contrast agents, process for producing them and their use as diagnostic and therapeutic agents |
JP1501696A JP2907911B2 (en) | 1988-02-05 | 1989-02-01 | Ultrasound contrast agent, method for producing the same, and diagnostic or therapeutic preparation comprising the ultrasound contrast agent |
IE940809A IE940809L (en) | 1988-02-05 | 1989-02-03 | Ultrasonic contrast agents, process for their preparation¹and their use as diagnostic and therapeutic agents |
IL89175A IL89175A (en) | 1988-02-05 | 1989-02-03 | Ultrasonic contrast agents and processes for the preparation thereof |
CA000590059A CA1336164C (en) | 1988-02-05 | 1989-02-03 | Ultrasonic contrast agents, process for their preparation and their use as a diagnostic and therapeutic agent |
PT89635A PT89635B (en) | 1988-02-05 | 1989-02-03 | PROCESS FOR THE PREPARATION OF CONTRASTS FOR ULTRASSONS |
ZA89873A ZA89873B (en) | 1988-02-05 | 1989-02-03 | Ultrasonic contrast agents,process for their preparation and their use as a diagnostic and therapeutic agent |
CN89100726A CN1033840C (en) | 1988-02-05 | 1989-02-04 | Ultrasonic contrast medium and application for diagnosis treatment |
MYPI89000146A MY105856A (en) | 1988-02-05 | 1989-02-04 | Ultra sonic contrast agents, process for their preparation and their use as diagnostic and therapeutic agents. |
NZ237900A NZ237900A (en) | 1988-02-05 | 1989-02-07 | Microparticles suitable as ultrasonic contrast agent comprising biodegradable polymers; preparation thereof |
NZ227869A NZ227869A (en) | 1988-02-05 | 1989-02-07 | Ultrasonic contrast agents containing amylose microparticles |
US07/536,373 US6264959B1 (en) | 1988-02-05 | 1990-06-11 | Ultrasonic contrast agents, process for their preparation and their use as a diagnostic and therapeutic agent |
FI903865A FI99086C (en) | 1988-02-05 | 1990-08-03 | Ultrasound contrast agents, methods for their preparation and their use as diagnostic agents |
DK199001864A DK175832B1 (en) | 1988-02-05 | 1990-08-03 | Ultrasonic contrast agents and methods for their preparation and their use |
NO903443A NO301260B1 (en) | 1988-02-05 | 1990-08-06 | Ultrasonic contrast agents and their use in the manufacture of a preparation for ultrasound diagnostics |
US08/474,468 US6177062B1 (en) | 1988-02-05 | 1995-06-07 | Agents and methods for enhancing contrast in ultrasound imaging |
US08/477,642 US6071496A (en) | 1988-02-05 | 1995-06-07 | Polyalkylcyanoacrylate agents and methods for enhancing contrast in ultrasound imaging |
JP7306254A JP3027326B2 (en) | 1988-02-05 | 1995-11-24 | Ultrasound contrast agent and ultrasonic diagnostic preparation |
NO970732A NO304412B1 (en) | 1988-02-05 | 1997-02-17 | Ultrasonic contrast agent and its use in the manufacture of a composition for ultrasound diagnostics |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3803971A DE3803971C2 (en) | 1988-02-05 | 1988-02-05 | Ultrasound contrast media |
Publications (2)
Publication Number | Publication Date |
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DE3803971C1 true DE3803971C1 (en) | 1989-09-07 |
DE3803971C2 DE3803971C2 (en) | 1997-09-18 |
Family
ID=6347026
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DE3803971A Expired - Lifetime DE3803971C2 (en) | 1988-02-05 | 1988-02-05 | Ultrasound contrast media |
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DE (1) | DE3803971C2 (en) |
ZA (1) | ZA89873B (en) |
Families Citing this family (1)
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GB9221329D0 (en) | 1992-10-10 | 1992-11-25 | Delta Biotechnology Ltd | Preparation of further diagnostic agents |
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US4265251A (en) * | 1979-06-28 | 1981-05-05 | Rasor Associates, Inc. | Method of determining pressure within liquid containing vessel |
US4276885A (en) * | 1979-05-04 | 1981-07-07 | Rasor Associates, Inc | Ultrasonic image enhancement |
EP0052575A2 (en) * | 1980-11-17 | 1982-05-26 | Schering Aktiengesellschaft | Composition generating microbubbles |
EP0122624A2 (en) * | 1983-04-15 | 1984-10-24 | Schering Aktiengesellschaft | Microparticles and ultrasonic contrast means containing gas bubbles |
EP0123235A2 (en) * | 1983-04-15 | 1984-10-31 | Schering Aktiengesellschaft | Microparticles and ultrasonic contrast means containing gas bubbles |
EP0224934A2 (en) * | 1985-12-05 | 1987-06-10 | Steven B. Feinstein | Contrast agent, process for its preparation and its use for ultrasonic imaging |
-
1988
- 1988-02-05 DE DE3803971A patent/DE3803971C2/en not_active Expired - Lifetime
-
1989
- 1989-02-03 ZA ZA89873A patent/ZA89873B/en unknown
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EP0052575A2 (en) * | 1980-11-17 | 1982-05-26 | Schering Aktiengesellschaft | Composition generating microbubbles |
EP0122624A2 (en) * | 1983-04-15 | 1984-10-24 | Schering Aktiengesellschaft | Microparticles and ultrasonic contrast means containing gas bubbles |
EP0123235A2 (en) * | 1983-04-15 | 1984-10-31 | Schering Aktiengesellschaft | Microparticles and ultrasonic contrast means containing gas bubbles |
EP0224934A2 (en) * | 1985-12-05 | 1987-06-10 | Steven B. Feinstein | Contrast agent, process for its preparation and its use for ultrasonic imaging |
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Derwent-Abstract 87-018962/03 (JP 61-2 77 610) * |
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DE3803971C2 (en) | 1997-09-18 |
ZA89873B (en) | 1989-10-25 |
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