CA1336164C - Ultrasonic contrast agents, process for their preparation and their use as a diagnostic and therapeutic agent - Google Patents

Ultrasonic contrast agents, process for their preparation and their use as a diagnostic and therapeutic agent

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Publication number
CA1336164C
CA1336164C CA000590059A CA590059A CA1336164C CA 1336164 C CA1336164 C CA 1336164C CA 000590059 A CA000590059 A CA 000590059A CA 590059 A CA590059 A CA 590059A CA 1336164 C CA1336164 C CA 1336164C
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Canada
Prior art keywords
ultrasonic contrast
microparticles
contrast agent
monomer
agent 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 - Fee Related
Application number
CA000590059A
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French (fr)
Inventor
Michael Stein
Dieter Heldmann
Thomas Fritzsch
Joachim Siegert
Georg Rossling
Ulrich Speck
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Bayer Pharma AG
Original Assignee
Schering AG
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Priority claimed from DE3803971A external-priority patent/DE3803971C2/en
Priority claimed from DE3803972A external-priority patent/DE3803972A1/en
Application filed by Schering AG filed Critical Schering AG
Application granted granted Critical
Publication of CA1336164C publication Critical patent/CA1336164C/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
    • 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

The invention relates to ultrasonic contrast agents consisting of microparticles which consist of amyloses and synthetic biodegradable polymers and a gas and/or a fluid with a boiling point below 60°C, process for the preparation thereof and their use as diagnostic and therapeutic agents.

Description

The invention relates to microparticles, a process for their preparation and their use as a diagnostic and therapeutic agent.

It is known that cardial echo contrasts can be achieved through peripheral injection of solutions which contain fine gas bubbles (Roelandt J, Ultrasound Med Biol 8: 471-492, 1982). These gas bubbles are obtained in physiologically compatible solutions, e.g. through shaking, other agitation or through the addition of carbon dioxide. However they are not standardized in terms of number and size and cannot be adequately reproduced. Also they are as a rule not stabilized so that their service life is short. Their average diameters are generally above the erythrocyte size so that it is not possible to obtain pulmonary capillary passages with subsequent contrasting of organs such as the left heart, liver, kidneys or spleen. Furthermore they are not suitable for quantifications since the ultrasonic echo which they produce is made up of from several processes which cannot be separated from each other such as the formation of the bubbles, coalescence and dissolution. Thus it is not possible for example to obtain definite details on the transit times with the aid of these ultrasonic contrast agents by measuring the contrast path in the myocardium.
This requires contrast agents whose dispersal bodies are not subject to their own kinetics.

In addition there are ultrasonic contrast agents in the form of particles (Ophir, Gobuty, McWhirt, Maklad, Ultrasonic Backscatter from Contrast-producing Collagen Microspheres, Ultrasonic Imaging 2:66-67, 1980). Furthermore solutions of a higher density are used as ultrasonic contrast agents (Ophir, McWhirt, Maklad, Aqueous Solutions as Potential Ultrasonic Contrast Agents, Ultrasonic Imaging 1:265-279, - 2 _ l 336 1 64 1979 as well as Tyler, Ophir, Maklad, In-vivo Enhancement of Ultrasonic Image Luminance by Aqueous Solutions with High Speed of Sound, Ultrasonic Imaging 3:323-329, 1981). It is also known to use emulsions as ultrasonic contrast agents (Mattrey, Andre, Ultrasonic Enhancement of Myocardial Infarction with Perfluorocarbon Compounds in Dogs, Am]
Cardiol 54: 206-210, 1984).

It has been seen that overall the gas-free contrast agents only have a low efficiency. The gas-cont~in;ng preparations have the disadvantage of only a slight in-vivo stability.
Furthermore the size of the gas bubbles can generally not be standardized. As a rule adequate contrast effects are not possible in the arterial vessel system after a peripheral veinous injection.

In EP A2 123 235, October 31, 1984 and 0 122 624, October 24, 1984 ultrasonic contrast agents are described which contain small gas bubbles and which pass through the pulmonary capillaries producing the-desired contrast effect.

EP A2 0 224 934, June 10, 1987 describes ultrasonic contrast agents in the form of gas-filled gelatine or albumin hollow bodies. However the disadvantage here is the use of foreign-body albumens or denatured albumens belonging to the body and thus the associated risk of allergy.

With none of the ultrasonic contrast agents known up until now is it possible to represent the organs with sufficient signal intensity through selective concentration after an i.v. dose. Quantifications are therefore not possible at the present time.

_ 3 _ l 336 1 64 The present invention provides ultrasonic contrast agents on the basis of microparticles which in addition to a determinable and reproducible volume have a considerably longer service life than previously known, offer good compatibility without allergic potential and can be concentrated intracellularly in RES and thus also in the liver or spleen.

In accordance with the invention there is provided by micro particles which consist of amylose or a synthetic biodegradable polymer and a gas and/or a fluid with a boiling point below 60C.

Polyesters of ~ or ~-hydroxy carbonic acids, polyalkylcyanoacrylates, polyamino acids, polyamides, polyacrylated saccharides or polyorthoesters are named as synthetic biodegradable polymers.

The following have proved particularly suitable:

Polylactic acid, Poly-~-caprolacton, Copolymers of lactic acid and glycol acid or ~-caprolacton, Polyhydroxybutyric acid, Polyhydroxyvaleric acid, Copolymers of hydroxybutyric and hydroxyvaleric acid, Polymers of glutamic acid and/or lysine Polydioxanon, Polymers or copolymers of amino acids and/or terephthalic acid, phthalic acid or sebacic acid, Polyacryldextran, Polyacryl starch, Polyacrylamide, Polyurethane, - 3a -Polyester, Polyacetal, Polyaminotriazol or Polyalkylcyanoacrylate.

a Starch or starch derivatives can also be contained in the microparticles. Amyloses have proved particularly suitable since these starch derivatives have excellent water solubility and the ability to form inclusion compounds.

s Amyloses which are particularly suitable are the cyclodextrins and their derivatives, by way of example ~, and~ -cyclodextrin.

The microparticles contain gases and/or fluids with a boiling point below 60 in free or bonded form. The use of a gas-fluid mixture in the ultrasonic contrast agents is likewise possible.

Gases used can be for example air, nitrogen, inert gases, hydrogen, carbon dioxide, ammonia, oxygen, methane, ethane, propane, butane, ethylene or other hydrocarbons or their mixtures.

Preferred fluids which can be included are:
1,1-dichloroethylene, 2-methyl-2-butene, isopropyl chloride, 2-methyl-1,3-butadiene, 2-butyne, 2-methyl-1-butene, 1 3361 ~4 dibromodifluoromethane, furan, 3-methyl-1-butene, isopentans, diethylether, 3,3-dimethyl-1-butyne, dimethylaminoacetone, propylene oxide, N-ethylmethylamine, bromomethane, n-athyldimethylamine, methylene chloride, pentane, cyclopentane, 2,3-pentadiene, cyclopentene, or mixtures thereof.

The microparticles can also contain advantageously substances with low steam pressures and/or low boiling points, in particular ethereal oils.

It is particularly advantageous to coat the microparticles which consist of amylose with a coating substance. The microparticles can thereby be encased in oils, fats and/or surface-active substances and suspended in an aqueous medium.

1 336 ~ 64 It is particularly advantageous to encase the microparticles which consist of amylose in a matrix, more particularly of a polymer structure.

The physiological isotony can be set by the addition of osmotically active substances such as cooling salt, galactose, glucose, fructose.

An advantageous process for preparing the ultrasonic contrast agents according to the invention consists in dissolving a polymer or copolymer in one or more organic solvents which are not miscible with water, followed by the emulsification in water, possibly with the addition of a further solvent, and then filtering and if required drying the emulsion obtained.

A further process consists in dissolving a polymer or copolymer in one or more solvents which contain gas bubbles, after which it is precipitated or amulsified in water, if required within the addition of a further solvent or a further polymer, and then the suspension or emulsion which has been obtained is then filtered and if required dried.
The freeze-drying process is also suitable as a finishing process.

The products obtained can advantageously be finely ground.

In the processes described, the solvents used can be for example furan, pentans, acetone, dioxan, ethyl acetate, xylol, methylene chloride, cyclohexane or hexane or solvent mixtures. Emulsifiers can also be added to the emulsion.

In a further variation of the manufacturing process instead of polymers monomers are used as the starting product from which the polymer is formed. With this process, a monomer is dissolved in one or more organic solvents and then emulsified in S - 30 parts water or 0.01 - 0.1 N hydrochloric acid, if required with the addition of emulsifiers or buffer substances at a temperature below the boiling point of the organic solvent, after which a 0.2% - 20% aqueous solution of a second monomer or if required the solution of a substance increasing the pH-value is added to this emulsion and dried if required.

In another method of operation a monomer is dissolved or dispersed in one or more fluids cont~;n;ng gas bubbles, if required with the addition or emulsifiers or buffer substances. If required a 0.2% - 20% solution of a second monomer or a substance increasing the pH-value in dissolved or gaseous form is added to this solution or dispersion and dried if required.

By way of example, terephthaloyl- or sebacoylchloride or cyanacrylic acid ester is used as a first monomer, L-lyaine as the second monomer and for example 2-methyl-1,3-butadiene, dioxan, methylene chloride, toluane or cyclohexane is used as the organic solvent.

According to a further process, the ultrasonic contrast agents are prepared by producing gas bubbles in a 0.5 - 10%
a~ueous solution or dispersion of a monomer which contains if required additives such as emulsifiers (0.01 - 5%) or ~uasi emulsifiers (0.1 - 5%), and then by adding a cross-linking substance and/or a reaction starter.

The ultrasonic contrast agents described above can be used for both diagnostic and therapeutic processes.

The application of the agents is for example by injection.

The invention will be explained by the following examples:

Example 1:

500 mg polylactide were dissolved in 4 ml furan and 0.6 ml cyclohexane and this solution was emulsified in 40 ml of a 0.1% solution of polyoxyethylene polyoxypropylene polymer with a molecular weight 12.000 (Pluronic ~ F 127), with the temperature being kept beneath 15C during emulsifying. The temperature was then slowly raised to evaporate off the organic solvent. The resulting suspension was then freeze-dried.

S Example 2 300 mg~-cyanoacrylic acid butyl ester were dissolved in 1 ml furan and this solution was emulsified in 10 ml 0.1 N
hydrochloric acid which contained 1% polyoxyethylene polyoxypropylene polymer with a molecular weight 12.000 (Pluronic ~ F 127), with the temperature being kept beneath 15C during emulsifying. At the end of polymerization the resulting suspension was freeze-dried.

Example 3 200 mg~-cyanoacrylic acid butyl ester were dissolved in 0.4 ml isoprene and emulsified in 30 ml 0.01 N hydrochloric acid which contained 1% polyoxyethylene polyoxypropylene polymer with a molecular weight 8.350 (Pluronic ~ F 68), with the temperature being kept beneath 10C during emulsifying.
At the end of polymerization the suspension was neutralized with 0.1 N NaOH and isotonized with sodium chloride.

Example 4 400 mg~-cyanoacrylic acid butyl ester dissolved in 0.4 ml methylene chloride and emulsified in 60 ml 0.01 N
hydrochloric acid which contained 1% polyoxyethylene polyoxypropylene polymer with a molecular weight 12.000 (Pluronic ~ F 127), with the temperature being kept beneath 10C during emulsifying. At the end of polymerization the suspension was neutralized with 0. 1 N soda lye and isotonized with sodium chloride.

ExamPle 5 400 mg polycaprolactone were dissolved in 6 ml furan and 0.3 ml cyclohexane and emulsified in 60 ml 1% polyoxyethylene polyoxypropylene polymer with molecular weight 12.000 (Pluronic ~ F 127), with the temperature being kept beneath 15C. The temperature was then slowly raised to evaporate off the organic solvent. The resulting suspension was then freeze-dried.

Example 6 400 mg terephthalic acid dichloride were dissolved in 2 ml furan and then emulsified in 50 ml 3~ sodium carbonate solution which contained 0.1% polyoxyethylene polyoxypropylene polymer with a molecular weight 12.000 (Pluronic ~ F 127). After the addition of 60 mg L-lysine, dissolved in 5 ml 0.1 % Pluronic F 127, the micro capsules were centrifuged and washed several times with 0.1% Pluronic F 127 solution. Before used the suspension was isotonized with sodium chloride.

Bx~mple 7 B-cyclodextrin-isopentane-inclusion compound:

100 ml saturated B-cyclodextrin solution (1.8%) were cooled to 10C and mixed with 3 ml isopentane. The resulting difficultly soluble complex was precipitated with constant stirring in the ultrasonic bath. The deposit was obtained in crystalline form through freeze-drying and filtration.
Isopentene content according to GC calculation: 0.25%.

Example 8 B-Cyclodextrin-2-methyl-2-butene-inclusion compounds:

100 ml saturated B-cyclodextrin solution (1.8%) were cooled to 10C and mixed with 3 ml 2-methyl-2-butene. The resulting difficultly soluble complex was precipitated with constant stirring in the ultrasonic bath. The deposit was obtained in crystalline form through freeze-drying and filtering.

ExamPle 9 ~-Cyclodextrin-2-methyl-1-butene-inclusioin compound:

S 100 ml saturated ~-cyclodextrin solution (1.8%) were cooled to lO-C and mixed with 3 ml 2-methyl-1-butene. The resulting difficultly soluble complex was precipitated with constant stirring in the ultrasonic bath. The deposit was obtained in crystalline form through freeze-drying and filtering. 2-methyl-l-butene content according to GC calculation: 0.82%.

Example 10 ~-cyclodextrin-isoprene-inclusion compound:

100 ml saturated ~-cyclodextrin solution (1.8%) were cooled to 10C and mixed with 3 ml isoprene. The resulting difficultly soluble complex was precipitated with constant stirring in the ultrasonic bath. The deposit was obtained in crystalline form through freeze-drying and filtering.
Isoprene content according to GC calculation: 1.0%.

~xample 11 ~-cyclodextrin-isopropylchloride-inclusion compound:

100 ml saturated ~-cyclodextrin solution (1.8%) were cooled to 10C and mixed with 3 ml isopropylchloride. The resulting difficultly soluble complex was precipitated with constant stirring in the ultrasonic bath. The deposit was obtained in crystalline form through freeze-drying and filtering.
Isopropylchloride content according to GC calculation: 0.5%.

Example 12 ~-cyclodextrin-isopentane-inclusion compound:

100 ml saturated ~-cyclodextrin solution (1.8%) were cooled to 10C and mixed with 3 ml isopentane. The resulting difficultly soluble complex was precipitated with constant stirring in the ultrasonic bath. The deposit was obtained in crystalline form through freeze-drying and filtering.

Example 13 Xenon/~-cyclodextrin-inclusion compound:

100 ml saturated ~-cyclodextrin solution (about 12%) were incubated under 7 atmospheres xenon for 7 days at room temperature in a 200 cc autoclave. The crystalline adduct could be sucked off, washed with cold water and dried via calcium chloride in the sxsiccator.

BxamPle 14 Carbon dioxide/~-cyclodextrin-inclusion compound:

100 ml saturated ~-cyclodextrin solution (about 12~) were incubated for 7 days at room temperature under 7 atmospheres carbon dioxide in a 20 cc autoclave. The crystalline adduct could be drawn off, washed with cold water and dried via calcium chloride in the sxsiccator.

Example 15 Isopentane/hydroxypropyl-~-cyclodextrin-inclusion compound:

15 ml 20% hydroxypropyl-~-cyclodextrin solution were mixed with 2 ml isopentane at 10C, ultrasounded for 3 minutes in the ultrasonic bath and then incubated for 26 hours. The resulting complex remained in solution.

ExamPle 16 Isoprene/hydroxypropyl-~-cyclodextrin inclusion compound:

15 ml 20% hydroxypropyl-~-cyclodextrin solution were mixed with 2 ml isoprene at 10C, ultrasounded for 3 minutes in the ultrasonic bath and then incubated for 26 hours. The resulting complex remained partly in solution andprecipitated partly as a white deposit.

Example 17 s Furan/hydroxypropyl-~-cyclodextrin-inclusion compound:

15 ml 20% hydroxypropyl-~-cyclodextrin solution were mixed with 2 ml furan at 10C, ultrasounded for 3 minutes in the ultrasonic bath and then incubated for 26 hours. The resulting complex remained partly in solution and partly precipitated as a white deposit.

Example 18 Isopentane/~-cyclodextrin-inclusion compound:

20 ml saturated n-cyclodextrin solution were mixed with 1 ml isopentane and ultrasounded for 3 minutes in the ultrasonic bath. The resulting difficultly soluble complex was obtained through filtration and dried via calcium chloride.

Example 19 Isoprene/~-cyclodextrin inclusion compound:

1 336 1 ~4 20 ml saturated ~-CD-solution were mixed with 1 ml isoprene and ultrasounded for 3 minutes in the ultrasonic bath. The resulting difficultly soluble complex was obtained through filtration and dried via calcium chloride.

Example 20 Furan/~-cyclodextrin-inclusion compound:

20 ml saturated a-cyclodexrin solution were mixed with 1 ml furan and ultrasounded for 3 minutes in the ultrasonic bath.
The resulting difficultly soluble complex was obtained through filtration and dried via calcium chloride.

lS The following applies to Examples 7 - 20:

The crystalline deposit was absorbed after cleaning in a suitable aqueous medium, preferably physiological cooking salt, glucose or Ringer solution and was then ready for injection.

Example 21 4 g eucalyptol was added dropwise to 100 ml saturated ~-cyclodextrin-solution (5C) in an incubation chamber while being ultrasounded and was ultrasounded for a further 30 min.

1336 1 ~4 Thereafter the residue was shaken in a cooled, closed vesselfor 48 hours. The resulting precipitate was extracted by filtration, washed with cold ethanol, frozen in liquid nitrogen and freeze-dried.

Bxample 22 100 ml saturated ~-cyclodextrin-solution was ultrasounded with 2 g Geraniol at 5C for 4 hours and thereafter incubated for 24 hours at 5C. The resulting precipitate was filtered off, washed with cold ethanol, frozen in liquid nitrogen and freeze-dried.

Claims (18)

1. Ultrasonic contrast agent comprising microparticles characterized in that the microparticles consist of amyloses and a gas and/or an organic fluid with a boiling point below 60°C or of synthetic biodegradable polymers and a gas and/or a fluid with a boiling point below 60°C.
2. Ultrasonic contrast agent according to claim 1, characterized in that the microparticles contain cyclodextrins or cyclodestrin derivatives as amylose.
3. Ultrasonic contrast agent according to claim 1, characterized in that the microparticles contain polyesters of .alpha., .beta., ? or .epsilon.-hydroxycarbonic acids, polyalkylcyanoacrylates, polyamino acids, polyamides, polyacrylated saccharides or polyorthoesters as the synthetic biodegradable polymers.
4. Ultrasonic contrast agent according to any one of claims 1 to 3 characterized in that the microparticles contain as organic fluids with a boiling point below 60°C

1,1-dichloroethylene, 2-methyl-2-butene, isopropylchloride, 2-methyl-1,3-butadiene, 2-butyne, 2-methyl-1-butene, dibromodifluoromethane, furan, 3-methyl-1-butene, isopentane, diethylether, 3,3-dimethyl-1-butyne, dimethylamino acetone, propylene oxide, N-ethylmethylamine, bromomethane, N-ethyldimethyl amine, methylene chloride, pentane, cyclopentane, 2,3-pentadiene, cyclopentene or mixtures thereof.
5. Ultrasonic contrast agent according to any one of claims 1 - 3 characterized in that the microparticles contain as gases air, inert gases, nitrogen, oxygen, carbon dioxide, hydrogen, ammonia, ethylene, methane, ethane, propane or butane or mixtures thereof.
6. Ultrasonic contrast agent according to claim 1, characterized in that the microparticles contain ethereal oils.
7. Ultrasonic contrast agent according to any one of claims 1, 2 and 4 - 6, characterized in that the microparticles consisting of amyloses are coated with a hydrophobic covering substance which consists of oils, fats and/or surface-active substances and are suspended in aqueous medium.
8. Ultrasonic contrast agent according to claim 1 or 2, characterized in that the microparticles consisting of amyloses are covered by a matrix, in particular of polymer structure.
9. Ultrasonic contrast agent according to any one of claims 1 to 3 or 6, characterized in that the physiological isotony is set by the addition of osmotically active substances, more particularly cooking salt, mannite, galactose, glucose or fructose.
10. Process for the preparation of ultrasonic contrast agents with microparticles of synthetic biodegradable polymers according to claim 1, characterized in that a polymer or copolymer is dissolved in one or more organic solvents which are not miscible with water, and is then emulsified in water if required after the addition of a further solvent, and the emulsion thus obtained is then filtered and if necessary dried.
11. Process for the preparation of ultrasonic contrast agents with microparticles of synthetic biodegradable polymers according to claim 1, characterized in that a polymer or copolymer is dissolved in one or more solvents containing gas bubbles and is then precipitated or emulsified in water, if required after adding a further solvent or a further polymer and then the suspension or emulsion obtained is then filtered off and if required dried.
12. Process according to claim 10 or 11, characterized in that furan, pentane, acetone, dioxan, ethylacetate, p-xylol, methylene chloride, cyclohexane or n-hexane or a solvent mixture consisting thereof is used as the solvent.
13. Process according to claim 10 or 11, characterized in that an emulsifier is added to the emulsion.
14. Process for the preparation of ultrasonic contrast agents with microparticles of synthetic, biodegradable polymers according to claim 1, characterized in that a monomer is dissolved in one or more organic solvents and emulsified in 5-30 parts water or 0.01 - 0.1 N hydrochloric acid if required with the addition of emulsifiers or buffer substances at a temperature below boiling point of the organic solvent, and a 0.2 - 20% aqueous solution of a second monomer or if required the solution of a substance which raises the pH value is added to the emulsion and dried if required.
15. Process for the preparation of ultrasonic contrast agents with microparticles of synthetic diodegradable polymers according to claim 1, characterized in that a monomer is dissolved or dispersed in one or more fluids containing gas bubbles, if required with the addition of emulsifiers and/or buffer substances, and to this solution or dispersion is added if required a 0.2 - 20% solution of a second monomer or a substance which raises the pH value in dissolved or gaseous form, followed by drying if required.
16. Process according to claim 14 or 15, characterized in that terephthaloyl- or sebacoyl chloride or cyanoacrylic acid ester is used as the first monomer, L-lysine as the second monomer and 2-methyl-1,3-butadiene, methylene chloride, toluene, dioxan or cyclohexane is used as the organic solvent.
17. Process for the preparation of ultrasonic contrast agents with microparticles of synthetic biodegradable polymers according to claim 1, 3 or 6, characterized in that gas bubbles are produced in a 0.5 - 10% aqueous solution of a monomer which contains if required additives such as emulsifiers (0.01 - 5%) or quasi-emulsifiers (0.1 - 5%) and then a cross-linking substance and/or a reaction starter is/are added.
18. Use of the ultrasonic contrast agent according to any one of claims 1 to 3 or 6 for diagnostic or therapeutic processes.
CA000590059A 1988-02-05 1989-02-03 Ultrasonic contrast agents, process for their preparation and their use as a diagnostic and therapeutic agent Expired - Fee Related CA1336164C (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE3803971A DE3803971C2 (en) 1988-02-05 1988-02-05 Ultrasound contrast media
DE3803972A DE3803972A1 (en) 1988-02-05 1988-02-05 Ultrasound contrast media
DEP3803971.0 1988-02-05
DEP3803972.9 1988-02-05

Publications (1)

Publication Number Publication Date
CA1336164C true CA1336164C (en) 1995-07-04

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US (3) US6264959B1 (en)
EP (3) EP0586875A1 (en)
JP (2) JP2907911B2 (en)
KR (1) KR0133132B1 (en)
CN (1) CN1033840C (en)
AT (1) ATE109663T1 (en)
AU (1) AU635200B2 (en)
CA (1) CA1336164C (en)
DE (1) DE58908194D1 (en)
DK (1) DK175832B1 (en)
ES (1) ES2068917T3 (en)
FI (1) FI99086C (en)
HU (1) HU221485B (en)
IE (2) IE66912B1 (en)
IL (1) IL89175A (en)
MY (1) MY105856A (en)
NO (2) NO301260B1 (en)
NZ (1) NZ227869A (en)
PT (1) PT89635B (en)
WO (1) WO1989006978A1 (en)

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