WO1994001140A1 - Echographic contrast agent composition - Google Patents

Echographic contrast agent composition Download PDF

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Publication number
WO1994001140A1
WO1994001140A1 PCT/EP1993/001705 EP9301705W WO9401140A1 WO 1994001140 A1 WO1994001140 A1 WO 1994001140A1 EP 9301705 W EP9301705 W EP 9301705W WO 9401140 A1 WO9401140 A1 WO 9401140A1
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WO
WIPO (PCT)
Prior art keywords
gas bubble
micro gas
percent
preparations according
bubble preparations
Prior art date
Application number
PCT/EP1993/001705
Other languages
German (de)
French (fr)
Inventor
Rudolf Linder
Klaus-Dieter Beller
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik Gmbh filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority to AU45630/93A priority Critical patent/AU4563093A/en
Publication of WO1994001140A1 publication Critical patent/WO1994001140A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres

Definitions

  • the invention relates to reconstitutable microbubble preparations for use as echo contrast agents in aqueous systems.
  • aqueous preparations containing stabilized micro gas bubbles were proposed early on as contrast agents for ultrasound diagnostics.
  • Micro gas bubbles can be removed in aqueous preparations by reducing the surface tension, i.e. stabilize by adding suitable surfactants.
  • EP-B-0077752 states that aqueous solutions which contain a surfactant or a surfactant mixture and additionally a viscosity-increasing substance have advantageous contrast-generating properties.
  • WO 91/12283 specifies the production of gas-filled microcapsules, according to which a shell is produced around a liquid or solid core and, after the core has been removed, the shell is cured chemically or by heat.
  • preparations available which are reconstitutable i.e. H. can be provided as powders which can be taken up in water or aqueous solutions and can be administered directly after reconstitution without the need to incorporate gas.
  • reconstitutable echo contrast medium formulations are obtained in aqueous systems by using aqueous apolar emulsifiers containing parenterally compatible emulsifiers Liquids and 1ipid-soluble or water-insoluble scaffolders lyophilized.
  • the lyophilizates obtained are notable for excellent storage stability and, when reconstituted with water, give echo contrast media containing microbubbles, which are distinguished by a very small diameter of the microbubbles and their surprisingly high stability. Due to the small diameter of the microbubbles and their great stability, the echo contrast media according to the invention are not only suitable for a very detailed representation of the left heart, but also for displaying small volumes, such as for diagnosing peripheral vessels.
  • the invention therefore relates to aqueous gas systems which can be reconstituted microbubble formulations for use as echo contrast media, obtainable by lyophilizing aqueous emulsions containing parenterally compatible emulsifiers, apolar liquids and lipid-soluble or water-insoluble scaffolding agents.
  • parenterally compatible emulsifiers are understood to mean above all phospholipids and poloxamers.
  • the parenterally compatible emulsifiers are contained in the aqueous emulsions in an amount of 0.5 to 10 percent, preferably 2 to 6 percent.
  • Preferred poloxamers polyoxyethylene polyoxypropylene polymers
  • Poloxamers are available, for example under the trademark del Pluronics ® (Wyandotte Chemicals Corp.) in Han ⁇ . Percentages relate to weight / volume.
  • Suitable phospholipids are phosphatidylglycerols, phosphatidylinositols, phosphatidylethanolamines and phosphatidylserines and their lysoforms. Lysoforms are understood to mean negatively charged phospholipids that contain only one acyl residue. Lysoforms of the negatively charged phospholipids in which the acyl group is bonded to the oxygen of the carbon atom 1 of the glycerol molecule are preferred. The positions are preferably loxamers according to the invention are used in combination with a phospholipid.
  • suitable non-polar liquids are, for example, petroleum ether and fluorinated or chlorinated hydrocarbons.
  • Apolar liquids with a boiling point between 30 and 65 ° C. are preferred.
  • Preferred apolar liquids are methylene chloride and petroleum ether.
  • the apolar liquids are contained in the aqueous emulsions in an amount of 1 to 50 percent, preferably 8 to 25 percent.
  • Lipid-soluble or water-insoluble scaffolders are understood according to the invention to mean substances such as cholesterol or cyanoacrylates, with cholesterol being preferred.
  • the builders are contained in the aqueous emulsions in an amount of 0.05 to 10 percent, preferably 0.1 to 5 percent.
  • auxiliaries such as saccharides, sugar alcohols or sodium chloride can also be present in the preparations according to the invention.
  • Sucrose is preferred as the saccharide.
  • Mannitol is preferably used as the sugar alcohol.
  • Glycerol, mannitol and ammonium salts of amino acids, preferably glycine, have proven to be particularly suitable for adjusting the isotonicity of the preparations according to the invention.
  • the preparations according to the invention are distinguished from the prior art by the fact that after reconstitution they contain micro gas bubbles with high stability, which produce a long-lasting contrast and are also excellently suitable for the presentation of the left heart and even for the presentation of peripheral vessels.
  • the preparation of the preparations according to the invention is unproblematic.
  • the poloxa is expediently dissolved, if desired together with an auxiliary such as mannitol, in water.
  • the framework substance e.g. B. cholesterol
  • a suitable emulsifier such as. B. phosphatidyl glycerol
  • the aqueous phase is then introduced into the lipid phase with vigorous stirring. If necessary, the mixture is then homogenized until a particle size of less than 4 ⁇ m, preferably less than 2 ⁇ m, is reached. Particularly preferred are particle sizes in the order of up to 0.5 ⁇ .
  • the emulsion obtained is filled into vials and lyophilized in the usual way.
  • preparations according to the invention can be dosed at a lower level because of their increased productivity compared to the prior art.
  • the echo contrast agents according to the invention are respirable and are therefore excellently suited for left heart diagnosis.
  • the applicability of ultrasound imaging in cardiac diagnostics and the diagnosis of peripheral vessels is considerably expanded by the echo contrast media according to the invention. It should be particularly emphasized here that no additional gas has to be incorporated during the reconstitution.

Abstract

Micro-gas bubble compositions reconstitutable in aqueous systems and useful as echographic contrast agents are prepared by lyophilising aqueous emulsions which contain parenterally acceptable emulsifiers, apolar liquids and lipid-soluble or water-insoluble builders. These lyophilisates are characterised by a remarkable storage stability and when reconstituted with water they produce microbubble-containing echographic contrast agents characterised by microbubbles having a very small diameter and a surprisingly high stability.

Description

Echokontrastmittelzubereitung Echo contrast preparation
Technisches GebietTechnical field
Die Erfindung betrifft in wäßrigen Systemen rekonstituierbare ikrogasbläs- chen-Zubereitungen zur Verwendung als Echokontrastmittel.The invention relates to reconstitutable microbubble preparations for use as echo contrast agents in aqueous systems.
Stand der TechnikState of the art
Da Ultraschall von in Flüssigkeiten suspendierten Gasbläschen stark reflek¬ tiert wird, wurden als Kontrastmittel für die Ultraschalldiagnostik schon frühzeitig wäßrige Zubereitungen vorgeschlagen, die stabilisierte Mikrogas- bläschen enthalten. Mikrogasbläschen lassen sich in wäßrigen Zubereitungen durch Herabsetzung der Oberflächenspannung, d.h. durch Zusatz geeigneter Tenside stabilisieren.Since ultrasound is strongly reflected by gas bubbles suspended in liquids, aqueous preparations containing stabilized micro gas bubbles were proposed early on as contrast agents for ultrasound diagnostics. Micro gas bubbles can be removed in aqueous preparations by reducing the surface tension, i.e. stabilize by adding suitable surfactants.
In der EP-B-0077752 wird angegeben, daß wäßrige Lösungen, die ein Tensid oder ein Tensidgemisch und zusätzlich eine Viskositätserhöhende Substanz enthalten, vorteilhafte kontrasterzeugende Eigenschaften aufweisen.EP-B-0077752 states that aqueous solutions which contain a surfactant or a surfactant mixture and additionally a viscosity-increasing substance have advantageous contrast-generating properties.
In der WO 91/12283 wird die Herstellung von gasgefüllten Mikrokapseln ange¬ geben, wonach um einen flüssigen oder festen Kern eine Hülle produziert wird und nach Entfernung des Kerns die Hülle chemisch oder durch Hitze ge¬ härtet wird.WO 91/12283 specifies the production of gas-filled microcapsules, according to which a shell is produced around a liquid or solid core and, after the core has been removed, the shell is cured chemically or by heat.
In der Praxis ist es wünschenswert, Zubereitungen zur Verfügung zu haben, die in rekonstituierbarer Form, d. h. als in Wasser oder wässrigen Lösungen aufnehmbare Pulver, bereitgestellt werden können, die nach der Rekonstitu- tion direkt verabreicht werden können, ohne daß noch Gas eingearbeitet zu werden braucht.In practice, it is desirable to have preparations available which are reconstitutable, i.e. H. can be provided as powders which can be taken up in water or aqueous solutions and can be administered directly after reconstitution without the need to incorporate gas.
Es wurde nun überraschenderweise gefunden, daß in wäßrigen Systemen rekon¬ stituierbare Echokontrastmittelzubereitungen erhalten werden, indem man wässrige Emulsionen enthaltend parenteral verträgliche Emulgatoren, apolare Flüssigkeiten und 1ipidlösliche oder wasserunlösliche Gerüstbildner lyophi- lisiert. Die erhaltenen Lyophilisate zeichnen sich durch eine hervoragende Lagerstabilität aus und ergeben bei der Rekonstitution mit Wasser Mikro¬ bläschen enthaltende Echokontrastmittel, die sich durch einen sehr geringen Durchmesser der Mikrobläschen und deren überraschend hohe Stabilität aus¬ zeichnen. Die erfindungsgemäßen Echokontrastmittel eignen sich aufgrund des geringen Durchmessers der Mikrobläschen und deren großer Stabilität nicht nur zu einer sehr detailreichen Darstellung des linken Herzens, sondern auch zur Darstellung kleiner Volumina wie beispielsweise zur Diagnose peri- pherer Gefäße.It has now surprisingly been found that reconstitutable echo contrast medium formulations are obtained in aqueous systems by using aqueous apolar emulsifiers containing parenterally compatible emulsifiers Liquids and 1ipid-soluble or water-insoluble scaffolders lyophilized. The lyophilizates obtained are notable for excellent storage stability and, when reconstituted with water, give echo contrast media containing microbubbles, which are distinguished by a very small diameter of the microbubbles and their surprisingly high stability. Due to the small diameter of the microbubbles and their great stability, the echo contrast media according to the invention are not only suitable for a very detailed representation of the left heart, but also for displaying small volumes, such as for diagnosing peripheral vessels.
Beschreibung der ErfindungDescription of the invention
Gegenstand der Erfindung sind daher in wäßrigen Systemen rekonstituierbare Mikrogasbläschen-Zubereitungen zur Verwendung als Echokontrastmittel, er¬ hältlich durch Lyophilisierung von wässrigen Emulsionen enthaltend parente¬ ral verträgliche Emulgatoren, apolare Flüssigkeiten und 1ipidlösliche oder wasserunlösliche Gerüstbildner.The invention therefore relates to aqueous gas systems which can be reconstituted microbubble formulations for use as echo contrast media, obtainable by lyophilizing aqueous emulsions containing parenterally compatible emulsifiers, apolar liquids and lipid-soluble or water-insoluble scaffolding agents.
Weitere Gegenstände ergeben sich aus den Patentansprüchen.Further subjects emerge from the patent claims.
Für die erfindungsgemäßen Zwecke werden unter parenteral verträglichen Emulgatoren vor allem Phospholipide und Poloxamere verstanden. Die parente¬ ral verträglichen Emulgatoren sind in den wässrigen Emulsionen in einer Menge von 0,5 bis 10 Prozent, vorzugsweise 2 bis 6 Prozent enthalten. Als Poloxamere (Polyoxyethylenpolyoxypropylen-Polymere) werden solche mit einem mittleren Molekulargewicht von 8350 bis 14000 bevorzugt. Poloxamere sind z.B. unter dem Warenzeichen Pluronics® (Wyandotte Chemicals Corp.) im Han¬ del erhältlich. Prozentangaben beziehen sich jeweils auf Gewicht/Volumen.For the purposes of the invention, parenterally compatible emulsifiers are understood to mean above all phospholipids and poloxamers. The parenterally compatible emulsifiers are contained in the aqueous emulsions in an amount of 0.5 to 10 percent, preferably 2 to 6 percent. Preferred poloxamers (polyoxyethylene polyoxypropylene polymers) are those with an average molecular weight of 8,350 to 14,000. Poloxamers are available, for example under the trademark del Pluronics ® (Wyandotte Chemicals Corp.) in Han¬. Percentages relate to weight / volume.
Als Phospholipide kommen Phosphatidylglycerole, Phosphatidylinositole, Phosphatidylethanolamine und Phosphatidylserine und deren Lysofor en in Frage. Unter Lysoformen werden negativ geladene Phospholipide verstanden, die nur einen Acylrest enthalten. Bevorzugt sind Lysoformen der negativ ge¬ ladenen Phospholipide, bei denen die Acylgruppe am Sauerstoff des Kohlen¬ stoffatoms 1 des Glycerinmoleküls gebunden ist. Vorzugsweise werden die Po- loxameren erfindungsgemäß in Kombination mit einem Phospholipid eingesetzt.Suitable phospholipids are phosphatidylglycerols, phosphatidylinositols, phosphatidylethanolamines and phosphatidylserines and their lysoforms. Lysoforms are understood to mean negatively charged phospholipids that contain only one acyl residue. Lysoforms of the negatively charged phospholipids in which the acyl group is bonded to the oxygen of the carbon atom 1 of the glycerol molecule are preferred. The positions are preferably loxamers according to the invention are used in combination with a phospholipid.
Als apolare Flüssigkeiten kommen erfindungsgemäß beispielweise Petrolether und fluorierte oder chlorierte Kohlenwasserstoffe in Frage. Bevorzugt sind apolare Flüssigkeiten mit einem Kochpunkt zwischen 30 und 65°C. Bevorzugte apolare Flüssigkeiten sind Methylenchlorid und Petrolether. In den wäßrigen Emulsionen sind die apolaren Flüssigkeiten in einer Menge von 1 bis 50 Pro¬ zent, vorzugsweise 8 bis 25 Prozent enthalten.According to the invention, suitable non-polar liquids are, for example, petroleum ether and fluorinated or chlorinated hydrocarbons. Apolar liquids with a boiling point between 30 and 65 ° C. are preferred. Preferred apolar liquids are methylene chloride and petroleum ether. The apolar liquids are contained in the aqueous emulsions in an amount of 1 to 50 percent, preferably 8 to 25 percent.
Unter 1ipidlöslichen oder wasserunlöslichen Gerüstbildnern werden erfin¬ dungsgemäß Stoffe wie Cholesterin oder Cyanacrylate verstanden, wobei Cho- lesterin bevorzugt ist. Die Gerüstbildner sind in den wäßrigen Emulsionen in einer Menge von 0,05 bis 10 Prozent, vorzugsweise 0,1 bis 5 Prozent ent¬ halten.Lipid-soluble or water-insoluble scaffolders are understood according to the invention to mean substances such as cholesterol or cyanoacrylates, with cholesterol being preferred. The builders are contained in the aqueous emulsions in an amount of 0.05 to 10 percent, preferably 0.1 to 5 percent.
Gewünschtenfalls können in den erfindungsgemäßen Zubereitungen noch übliche Hilfsstoffe wie Saccharide, Zuckeralkohole oder Natriumchlorid enthalten sein. Als Saccharid wird Saccharose bevorzugt. Als Zuckeralkohol wird vor¬ zugsweise Mannit verwendet. Als besonders gut geeignet zur Einstellung der Isotonie der erfindungsgemäßen Zubereitungen haben sich Glycerin, Mannit und Ammoniumsalze von Aminosäuren, vorzugsweise Glycin, erwiesen.If desired, conventional auxiliaries such as saccharides, sugar alcohols or sodium chloride can also be present in the preparations according to the invention. Sucrose is preferred as the saccharide. Mannitol is preferably used as the sugar alcohol. Glycerol, mannitol and ammonium salts of amino acids, preferably glycine, have proven to be particularly suitable for adjusting the isotonicity of the preparations according to the invention.
Die erfindungsgemäßen Zubereitungen zeichnen sich gegenüber dem Stand der Technik dadurch aus, daß sie nach der Rekonstitution Mikrogasbläschen mit hoher Stabilität enthalten, die einen lang anhaltenden Kontrast erzeugen und sich ausgezeichnet auch zur Linksherzdarstellung und sogar zur Dar¬ stellung peripherer Gefäße eignen.The preparations according to the invention are distinguished from the prior art by the fact that after reconstitution they contain micro gas bubbles with high stability, which produce a long-lasting contrast and are also excellently suitable for the presentation of the left heart and even for the presentation of peripheral vessels.
Die Herstellung der erfindungsgemäßen Zubereitungen ist unproblematisch. Zweckmäßigerweise löst man das Poloxa er, gewünschtenfalls zusammen mit einem Hilfsstoff wie Mannit in Wasser. Die Gerüstsubstanz, z. B. Choleste- rin, wird zusammen mit einem geeigneten Emulgator, wie z. B. Phosphatidyl- glycerol, in dem apolaren Lösungsmittel gelöst. Die wässrige Phase wird so¬ dann unter starkem Rühren in die Lipidphase eingetragen. Erforderlichen¬ falls wird anschließend homogenisiert, bis eine Teilchengröße von weniger als 4 μm, vorzugsweise weniger als 2 μm, erreicht ist. Besonders bevorzugt sind Teilchengrößen in der Größenordnung von bis zu 0,5 μ . Man füllt die erhaltene Emulsion in Vials und lyophilisiert auf übliche Weise.The preparation of the preparations according to the invention is unproblematic. The poloxa is expediently dissolved, if desired together with an auxiliary such as mannitol, in water. The framework substance, e.g. B. cholesterol, together with a suitable emulsifier, such as. B. phosphatidyl glycerol, dissolved in the non-polar solvent. The aqueous phase is then introduced into the lipid phase with vigorous stirring. If necessary, the mixture is then homogenized until a particle size of less than 4 μm, preferably less than 2 μm, is reached. Particularly preferred are particle sizes in the order of up to 0.5 μ. The emulsion obtained is filled into vials and lyophilized in the usual way.
Besonders hervorzuheben ist, daß die erfindungsgemäßen Zubereitungen wegen ihrer im Vergleich zum Stand der Technik erhöhten Ergiebigkeit niedriger dosiert werden können.It should be emphasized in particular that the preparations according to the invention can be dosed at a lower level because of their increased productivity compared to the prior art.
Herstel1ungsbeispielManufacturing example
1. Man löst 30,0 g Poloxamer 188 und 54,0 g Mannit in 800 ml Wasser für Injektionszwecke. 30,0 g Phosphatidylglycerol und 20,0 g Cholesterin wer¬ den in 100,0 g Petrolether gelöst. Die wässrige Phase wird unter starkem Rühren in die Lipidphase eingetragen. Man füllt mit Wasser zur Injektion auf 1 Liter auf. Es wird anschließend so lange homogenisiert, bis eine Teilchengröße von weniger als 4 μm erreicht ist. Die erhaltene Emulsion wird in Vials abgefüllt und lyophilisiert.1. Dissolve 30.0 g of Poloxamer 188 and 54.0 g of mannitol in 800 ml of water for injections. 30.0 g of phosphatidylglycerol and 20.0 g of cholesterol are dissolved in 100.0 g of petroleum ether. The aqueous phase is introduced into the lipid phase with vigorous stirring. Make up to 1 liter with water for injection. It is then homogenized until a particle size of less than 4 μm is reached. The emulsion obtained is filled into vials and lyophilized.
2. Man löst in 700 ml Wasser für Injektionszwecke bei 50 bis 60°C 35,0 g Poloxamer 188, 25,0 g Dimyristoylphosphatidylglycerol und 100,0 g Saccha¬ rose. In einer Mischung aus 140 g Petrolether und 60,0 g Dichlormethan werden 10,0 g Cholesterin gelöst. Die wäßrige Phase wird unter starkem Rühren in die Lipidphase eingetragen. Man füllt mit Wasser für Injektions¬ zwecke auf einen Liter auf. Die Emulsion wird homogenisiert, bis die Teil- chengröße der inneren Phase <4 μm (bevorzugt <500 nm) ist. Die erhaltene Emulsion wird in Vials abgefüllt und lyophilisiert.2. Dissolve in 700 ml of water for injections at 50 to 60 ° C 35.0 g of Poloxamer 188, 25.0 g of dimyristoylphosphatidylglycerol and 100.0 g of saccharose. 10.0 g of cholesterol are dissolved in a mixture of 140 g of petroleum ether and 60.0 g of dichloromethane. The aqueous phase is introduced into the lipid phase with vigorous stirring. Make up to one liter with water for injections. The emulsion is homogenized until the particle size of the inner phase is <4 μm (preferably <500 nm). The emulsion obtained is filled into vials and lyophilized.
Aus den durchgeführten Untersuchungen ergibt sich, daß die erfindungsge¬ mäßen Echokontrastmittel im Gegensatz zu den Echokontrastmitteln nach dem Stand der Technik lungengängig sind und sich daher ausgezeichnet zur Links¬ herzdiagnostik eignen. Die Anwendbarkeit der Ultraschallbildgebung in der Herzdiagnostik und der Diagnostik peripherer Gefäße wird durch die erfin¬ dungsgemäßen Echokontrastmittel erheblich erweitert. Besonders hervorzu¬ heben ist hierbei, daß bei der Rekonstitution kein zusätzliches Gas einge¬ arbeitet werden muß. The investigations carried out show that, in contrast to the echo contrast agents according to the prior art, the echo contrast agents according to the invention are respirable and are therefore excellently suited for left heart diagnosis. The applicability of ultrasound imaging in cardiac diagnostics and the diagnosis of peripheral vessels is considerably expanded by the echo contrast media according to the invention. It should be particularly emphasized here that no additional gas has to be incorporated during the reconstitution.

Claims

Patentansprüche Claims
1. In wäßrigen Systemen rekonstituierbare Mikrogasbläschen-Zubereitungen zur Verwendung als Echokontrastmittel, erhältlich durch Lyophilisierung von wäßrigen Emulsionen enthaltend parenteral verträgliche Emulgatoren, apolare Flüssigkeiten und lipidlösliche oder wasserunlösliche Gerüstbildner.1. Reconstitutable micro gas bubble preparations for use as echo contrast media, obtainable by lyophilization of aqueous emulsions containing parenterally compatible emulsifiers, apolar liquids and lipid-soluble or water-insoluble scaffolders.
2. Mikrogasbläschen-Zubereitungen nach Anspruch 1, dadurch gekennzeichnet, daß als parenteral verträgliche Emulgatoren Phospholipide und/oder Poloxa¬ mere enthalten sind.2. Micro gas bubble preparations according to claim 1, characterized in that phospholipids and / or poloxamers are contained as parenterally compatible emulsifiers.
3. Mikrogasbläschen-Zubereitungen nach Anspruch 2, dadurch gekennzeichnet, daß Phosphatidylglycerol und/oder Poloxamer 188 enthalten sind.3. Micro gas bubble preparations according to claim 2, characterized in that phosphatidylglycerol and / or poloxamer 188 are contained.
4. Mikrogasbläschen-Zubereitungen nach Anspruch 1, dadurch gekennzeichnet, daß als Gerüstbildner Cholesterin und/oder Cyanacrylate enthalten sind.4. Micro gas bubble preparations according to claim 1, characterized in that cholesterol and / or cyanoacrylates are contained as a scaffold.
5. Mikrogasbläschen-Zubereitungen nach Anspruch 1, dadurch gekennzeichnet, daß als apolare Flüssigkeiten Petrolether und/oder fluorierte bzw. chlo¬ rierte Kohlenwasserstoffe eingesetzt werden.5. Micro gas bubble preparations according to claim 1, characterized in that petroleum ether and / or fluorinated or chlorinated hydrocarbons are used as apolar liquids.
6. Mikrogasbläschen-Zubereitungen nach Anspruch 1, dadurch gekennzeichnet, daß in der wässrigen Emulsion 0,5 bis 10, vorzugsweise 2 bis 6 Prozent (Ge¬ wicht/Volumen) parenteral verträgliche Emulgatoren enthalten sind.6. Micro gas bubble preparations according to claim 1, characterized in that the aqueous emulsion contains 0.5 to 10, preferably 2 to 6 percent (weight / volume) parenterally compatible emulsifiers.
7. Mikrogasbläschen-Zubereitungen nach Anspruch 1, dadurch gekennzeichnet, daß in der wäßrigen Emulsion 0,05 bis 10, vorzugsweise 0,1 bis 5 Prozent (Gewicht/Volumen) Gerüstbildner enthalten sind.7. micro gas bubble preparations according to claim 1, characterized in that the aqueous emulsion contains 0.05 to 10, preferably 0.1 to 5 percent (weight / volume) scaffold.
8. Mikrogasbläschen-Zubereitungen nach Anspruch 1, dadurch gekennzeichnet, daß in der wässrigen Emulsion 1 bis 50, vorzugsweise 8 bis 25 Prozent (Ge¬ wicht/Volumen) apolare Flüssigkeit enthalten sind.8. Micro gas bubble preparations according to claim 1, characterized in that the aqueous emulsion contains 1 to 50, preferably 8 to 25 percent (weight / volume) apolar liquid.
9. Mikrogasbläschen-Zubereitungen nach Anspruch 1 erhältlich durch Lyophi¬ lisierung einer wäßrigen Emulsion enthaltend 3 Prozent Poloxamer 188,9. Micro gas bubble preparations according to claim 1 obtainable by lyophilizing an aqueous emulsion containing 3 percent poloxamer 188,
3 Prozent Phosphatidylglycerol, 2 Prozent Cholesterin, 10 Prozent Petrol¬ ether und 54 Prozent Mannit. 3 percent phosphatidylglycerol, 2 percent cholesterol, 10 percent petroleum ether and 54 percent mannitol.
10. Verfahren zur Herstellung von Mikrogasbläschen-Zubereitungen nach An¬ spruch 1, dadurch gekennzeichnet, daß man den parenteral verträglichen Emulgator in Wasser löst, die Gerüstsubstanz zusammen mit einem geeigneten Emulgator in dem apolaren Lösungsmittel löst, die wäßrige Phase unter star¬ kem Rühren in die nichtwäßrige Phase einträgt, homogenisiert bis eine Teil¬ chengröße von weniger als 2 μm erreicht ist, die erhaltene Emulsion in Vials abfüllt und lyophilisiert. 10. A process for the preparation of micro gas bubble preparations according to claim 1, characterized in that the parenterally compatible emulsifier is dissolved in water, the framework substance is dissolved in the nonpolar solvent together with a suitable emulsifier, and the aqueous phase is stirred in with vigorous stirring the non-aqueous phase is introduced, homogenized until a particle size of less than 2 μm is reached, the emulsion obtained is filled into vials and lyophilized.
PCT/EP1993/001705 1992-07-03 1993-07-02 Echographic contrast agent composition WO1994001140A1 (en)

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WO1995021631A1 (en) * 1994-02-15 1995-08-17 Nycomed Imaging As Improvements in or relating to contrast agents
US5540909A (en) * 1994-09-28 1996-07-30 Alliance Pharmaceutical Corp. Harmonic ultrasound imaging with microbubbles
US5605673A (en) * 1993-07-30 1997-02-25 Alliance Pharmaceutical Corp. Stabilized microbubble compositions for ultrasound
EP0818989A1 (en) * 1995-04-05 1998-01-21 Imarx Pharmaceutical Corp. Novel compositions of lipids and stabilizing materials
US5798091A (en) * 1993-07-30 1998-08-25 Alliance Pharmaceutical Corp. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
US5804162A (en) * 1995-06-07 1998-09-08 Alliance Pharmaceutical Corp. Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients
WO1999008715A1 (en) * 1997-08-19 1999-02-25 Nycomed Imaging As Process for preparing contrast agents
US9248204B2 (en) 2004-08-18 2016-02-02 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
US9364569B2 (en) * 2003-02-04 2016-06-14 Bracco Suisse S.A. Ultrasound contrast agents and process for the preparation thereof
US9750821B2 (en) 2003-12-22 2017-09-05 Bracco Suisse S.A. Gas-filled microvesicle assembly for contrast imaging

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