WO1994001140A1 - Composition d'agents de contraste echographique - Google Patents

Composition d'agents de contraste echographique 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
Authority
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)
English (en)
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/fr

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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.

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  • Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Acoustics & Sound (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

On prépare des compositions contenant des microbulles de gaz, reconstituables dans des systèmes aqueux et utiles comme agents de contraste échographique, par lyophilisation d'émulsions aqueuses contenant des émulsifiants admissibles pour administration parentérale, des liquides apolaires et des adjuvants solubles dans des lipides ou insolubles dans l'eau. Ces lyophilisés se caractérisent par une remarquable stabilité au stockage et permettent d'obtenir, lorsqu'ils sont reconstitués avec de l'eau, des agents de contraste échographique contenant des microbulles qui se caractérisent par des microbulles ayant un diamètre très réduit et une stabilité étonnamment élévée.
PCT/EP1993/001705 1992-07-03 1993-07-02 Composition d'agents de contraste echographique WO1994001140A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU45630/93A AU4563093A (en) 1992-07-03 1993-07-02 Echographic contrast agent composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH02090/92-3 1992-07-03
CH209092 1992-07-03

Publications (1)

Publication Number Publication Date
WO1994001140A1 true WO1994001140A1 (fr) 1994-01-20

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/001705 WO1994001140A1 (fr) 1992-07-03 1993-07-02 Composition d'agents de contraste echographique

Country Status (2)

Country Link
AU (1) AU4563093A (fr)
WO (1) WO1994001140A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995021631A1 (fr) * 1994-02-15 1995-08-17 Nycomed Imaging As Perfectionnements relatifs a des agents de contraste
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 (fr) * 1995-04-05 1998-01-21 Imarx Pharmaceutical Corp. Compositions nouvelles de lipides et de materiaux de stabilisation
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 (fr) * 1997-08-19 1999-02-25 Nycomed Imaging As Procede de preparation de milieux de contraste
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

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5126213A (ja) * 1974-08-21 1976-03-04 Tanabe Seiyaku Co Johoseibiryushiseizaino seiho
EP0077752A2 (fr) * 1981-10-16 1983-04-27 Schering Aktiengesellschaft Mélange liquide pour l'absorption et la stabilisation de vésicules de gaz utilisée comme agent de contraste pour le diagnostic par ultrasons et son procédé de préparation
US4684479A (en) * 1985-08-14 1987-08-04 Arrigo Joseph S D Surfactant mixtures, stable gas-in-liquid emulsions, and methods for the production of such emulsions from said mixtures
WO1991012823A1 (fr) * 1990-02-20 1991-09-05 Delta Biotechnology Limited Aide au diagnostic

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5126213A (ja) * 1974-08-21 1976-03-04 Tanabe Seiyaku Co Johoseibiryushiseizaino seiho
EP0077752A2 (fr) * 1981-10-16 1983-04-27 Schering Aktiengesellschaft Mélange liquide pour l'absorption et la stabilisation de vésicules de gaz utilisée comme agent de contraste pour le diagnostic par ultrasons et son procédé de préparation
US4684479A (en) * 1985-08-14 1987-08-04 Arrigo Joseph S D Surfactant mixtures, stable gas-in-liquid emulsions, and methods for the production of such emulsions from said mixtures
WO1991012823A1 (fr) * 1990-02-20 1991-09-05 Delta Biotechnology Limited Aide au diagnostic

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 85, no. 4, 26 July 1976, Columbus, Ohio, US; abstract no. 25402a, "Long-acting drug particles." *

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6706253B2 (en) 1993-07-30 2004-03-16 Ernest G. Schutt Osmotically stabilized microbubble preparations
US5639443A (en) * 1993-07-30 1997-06-17 Alliance Pharmaceutical Corp. Stabilized microbubble compositions
US6280705B1 (en) 1993-07-30 2001-08-28 Alliance Pharmaceutical Corp. Kits & systems for ultrasonic imaging
US5626833A (en) * 1993-07-30 1997-05-06 Alliance Pharmaceutical Corp. Ultrasound imaging method using microbubbles
US5798091A (en) * 1993-07-30 1998-08-25 Alliance Pharmaceutical Corp. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
US5695741A (en) * 1993-07-30 1997-12-09 Alliance Pharmaceutical Corp. Stable microbubble precursors
US7005120B2 (en) 1993-07-30 2006-02-28 Imcor Pharmaceutical Company Osmotically stabilized microbubble preparations
US6953569B2 (en) 1993-07-30 2005-10-11 Imcor Pharmaceutical Company Mixed gas microbubble compositions
US5605673A (en) * 1993-07-30 1997-02-25 Alliance Pharmaceutical Corp. Stabilized microbubble compositions for ultrasound
US7141235B2 (en) 1993-07-30 2006-11-28 Imcor Pharmaceutical Co. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
US5720938A (en) * 1993-07-30 1998-02-24 Alliance Pharmaceutical Corp. Systems for the formation of microbubbles
US6939531B2 (en) 1993-07-30 2005-09-06 Imcor Pharmaceutical Company Ultrasonic imaging system utilizing a long-persistence contrast agent
US6258339B1 (en) 1993-07-30 2001-07-10 Alliance Pharmaceutical Corp. Osmotically stabilized microbubble preparations
US6372195B1 (en) 1993-07-30 2002-04-16 Alliance Pharmaceutical Corp. Mixed gas microbubble compositions
US6287539B1 (en) 1993-07-30 2001-09-11 Alliance Pharmaceuticals Corp. Methods of imaging using osmotically stabilized microbubble preparations
US6280704B1 (en) 1993-07-30 2001-08-28 Alliance Pharmaceutical Corp. Ultrasonic imaging system utilizing a long-persistence contrast agent
WO1995021631A1 (fr) * 1994-02-15 1995-08-17 Nycomed Imaging As Perfectionnements relatifs a des agents de contraste
US5733527A (en) * 1994-09-28 1998-03-31 Alliance Pharmaceutical Corp. Methods for harmonic imaging with ultrasound
US5540909A (en) * 1994-09-28 1996-07-30 Alliance Pharmaceutical Corp. Harmonic ultrasound imaging with microbubbles
US6019960A (en) * 1994-09-28 2000-02-01 Alliance Pharmaceutical Corp. Systems for harmonic ultrasound imaging
US6056943A (en) * 1994-09-28 2000-05-02 Alliance Pharmaceutical Corp. Methods of ultrasound imaging using phospholipid stabilized microbubbles
US6036644A (en) * 1994-09-28 2000-03-14 Alliance Pharmaceutical Corp. Enhanced methods of ultrasound imaging using multiple frequencies
EP0818989A4 (fr) * 1995-04-05 2000-09-13 Imarx Pharmaceutical Corp Compositions nouvelles de lipides et de materiaux de stabilisation
EP0818989A1 (fr) * 1995-04-05 1998-01-21 Imarx Pharmaceutical Corp. Compositions nouvelles de lipides et de materiaux de stabilisation
US5804162A (en) * 1995-06-07 1998-09-08 Alliance Pharmaceutical Corp. Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients
US6193952B1 (en) 1995-06-07 2001-02-27 Alliance Pharmaceutical Corp. Stabilized gas emulsions containing phospholipid for ultrasound contrast enhancement
US6509004B1 (en) 1997-08-19 2003-01-21 Amersham Health As Process for preparing contrast agents
WO1999008715A1 (fr) * 1997-08-19 1999-02-25 Nycomed Imaging As Procede de preparation de milieux de contraste
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
US9248204B2 (en) 2004-08-18 2016-02-02 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
US10076580B2 (en) 2004-08-18 2018-09-18 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging

Also Published As

Publication number Publication date
AU4563093A (en) 1994-01-31

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