WO1997026016A2

WO1997026016A2 - Gas bubble suspensions and their application as an ultrasound contrast medium

Info

Publication number: WO1997026016A2
Application number: PCT/EP1997/000208
Authority: WO
Inventors: Martina Bergmann; Dieter Heldmann; Werner Weitschies; Thomas Fritzsch; Violetta Sudmann
Original assignee: Schering Aktiengesellschaft
Priority date: 1996-01-18
Filing date: 1997-01-16
Publication date: 1997-07-24
Also published as: WO1997026016A3; AU1592597A; NO983332D0; NO983332L; DE19602930A1; JP2000504317A; EP0874644A2; CA2243174A1; ZA97414B

Abstract

The invention concerns porous matrices of low molecular substances for generating stable gas bubble suspensions, their application as an ultrasound contrast medium and the process for producing the matrices and medium.

Description

GAS BUBBLE SUSPENSIONS AND THEIR USE AS ULTRASONIC CONTRASTS

The invention relates to the subject characterized in the claims, that is to say porous matrices for generating stable gas bubble suspensions, their use as ultrasound contrast agents and methods for producing the matrices and agents.

Ultrasound diagnostics offer the possibility of diagnosing physiological and pathophysiological conditions without stressful ionizing radiation as in X-ray or radionuclide examinations and relatively inexpensively compared to magnetic resonance imaging. Ultrasonic waves are reflected or absorbed depending on the acoustic properties of the tissue. Different acoustic properties of tissues and body fluids are used for imaging. Due to the large density difference between body tissue or body fluids on the one hand and gas bubbles on the other hand, gases in the form of microbubbles are particularly suitable as contrast agents for ultrasound. Ultrasound contrast agents are therefore essentially researched and developed on the basis of gas bubbles and / or substances containing gas.

The simplest type of ultrasound contrast medium can be obtained by methods such as shaking, sonicating or pumping around an aqueous suspension medium between two syringes. The introduced bubbles can be made by suitable

Additives such as surfactants and / or viscosity-increasing substances are stabilized. Such contrast agents are e.g. described in EP 0 077 752. The strong dependence of the number and size of gas bubbles on the type, duration and intensity of the agitation is problematic. This makes the production difficult to reproduce and the risk of an embolism due to excessive gas bubbles is uncontrollable.

A similar type of contrast medium is described in WO 93/05819, but instead of the atmospheric gases such as air, nitrogen, carbon dioxide and noble gases, gases with a certain Q factor are proposed for the preparation of the bladder suspensions. These are usually halogenated hydrocarbons that are characterized by low solubility in physiological media. Perfluorinated compounds in particular are suitable as exchange gases. However, in this case too - as described above - the If bladder suspension is introduced into the suspension medium by pumping between two syringes via a three-way valve, these agents show an inhomogeneous and poorly reproducible bubble size distribution. This increases the risk of embolism due to gas bubbles that are too large.

In addition to the possibility of producing the gas bubble suspension directly before use by agitation of the medium, solid carriers can also be formulated, from which bubbles are released after resuspending in a suitable diluent. A microparticle suspension is used here. Such solid carriers can be microparticles which consist, for example, of a mixture of at least one surface-active substance with at least one non-surface-active solid, as are disclosed in EP 0 365 467.

In addition to the substances mentioned in EP 0 365 467, non-surface-active solids can also be substances which are used as X-ray contrast media (WO 93/00930 and WO 92/21382), in the case of the latter document the X-ray contrast media being crosslinked via functional groups and crosslinkers .

The microparticle suspensions mentioned are ultrasound contrast media with which contrast effects can be achieved in the arterial system. Contrast intensity and duration seem to be in need of improvement.

Further examples of microparticulate ultrasound contrast agents are disclosed in WO 95/21631. Here water-insoluble wall formers are dissolved in an organic solvent (toluene), then emulsified in an aqueous surfactant solution and freeze-dried. By resuspending a microparticle suspension is obtained which shows ultrasound contrast in vivo. The use of certain fluorinated substances is also described for the type of microparticulate ultrasound contrast media.

For example, EP 0 554 213 discloses galactose-based microparticles which contain SFg instead of air. However, the contrast-enhancing effects for this remedy are weak.

WO 95/22994 also discloses microparticles containing fluorinated substances. The bubble size distribution is standardized and the number of bubbles significantly increased, see above that the dose required for an ultrasound contrast agent application can be considerably reduced.

WO 95/03835 claims ultrasound contrast agents based on particles which contain defined gas mixtures. The gas mixtures consist of at least one fluorinated, gas-osmotically active component and at least one conventional gas such as nitrogen, oxygen and / or carbon dioxide. The particles are made up of proteins, dextrins, starch and starch derivatives, e.g. Hydroxyethyl starch. As stated in the document, among the substances mentioned, those with a high molecular weight (> 500,000 daltons) are preferred, since otherwise the stabilization of the gas bubbles is inadequate. However, such substances cannot be filtered through the kidneys and must be broken down by the liver, among other things. This increases the dwell time in the body. The above-mentioned hydroxyethyl starch is broken down into substituted oligosaccharides which are primarily eliminated renally when the kidney threshold is undershot. The storage of hydroxyethyl starch in the cells of the reticuloendothelial system is discussed as a possible problem. The ethyl ether bond is not amenable to enzymatic degradation. The metabolism and elimination of hydroxyethylglucose, as well as their possible pharmacological effects, is currently not clear [Krech, I .; Wind, S. (1995) Krankenhauspharmazie 16 (2), 62-63]. In addition, because of their poorer solubility, higher molecular weight substances carry the risk that particulate portions of uncontrolled size are applied after resuspending the contrast medium preparation. The patient is at risk of embolism.

Fluorinated gases and air-containing particles are also claimed in WO 95/16467, the proportion of the fluorinated component here being limited to 41%.

WO 94/09829 describes ultrasound contrast agents containing liposomes. Phospholipids but also other surfactants which are difficult to dissolve in water are mentioned as gas bubbles stabilizing surfactant. Such liposomal systems are generally produced by lyophilization from freeze-dry solvents such as, for example, tertiary-butanol or C ₂ Cl ₄ F ₂ . The use of organic solvents to produce these agents requires a lot of effort

Solvent recovery and requires careful inspection of the product for residual solvent content. The halogenated hydrocarbons used as solvents, especially fluorinated ones Chlorinated hydrocarbons (CFCs) such as C ₂ C1 ₄ F ₂ are also extremely critical because of their ozone depleting potential.

The object of the present invention was therefore to provide compounds for the production of ultrasound contrast media which overcome the disadvantages of the prior art, i.e. the

• overcome the existing pharmaceutical and pharmacological problems, • which can be produced easily and without the use of organic solvents, generate a reproducible size and number of bubbles, in dissolved form lead to high contrast intensity, long-lasting contrast effects, have high bubble stability and, moreover, • can be filtered through the kidneys and are therefore quickly excreted.

This object is achieved by the present invention.

It has been found that preparations consisting of a porous, solid, water-soluble matrix containing a low molecular weight scaffold, a surfactant and a gas, the gas being enclosed in the pores of the matrix, are outstandingly suitable for producing a preparation for ultrasound diagnosis.

In contrast to the microparticulate contrast media of the prior art, the contrast media according to the invention are generated from a particle-free, porous, solid structure, which is referred to below as a porous matrix. To clarify the basic structural differences, reference is made to FIGS. 1 and 2. FIG. 1 shows a scanning electron microscope image of a microparticulate preparation of the prior art (EP 0 365 467), FIG. 2 shows an image of a preparation according to the invention produced according to Example 19 at the same magnification (1 cm in the figures corresponds to 1.1 μm in reality) . Clearly recognizable are the uniform pores from which gas bubbles are released after the matrix is dissolved. The size and number of pores are highly reproducible. The size of the bubbles is essentially limited by the pore size. The number of bubbles that can be released from the matrix is also determined by the porosity of the matrix. The parameters mentioned (bubble size and number) can be easily controlled via various production parameters and have an important influence on the effectiveness of the contrast medium. The formation of the gas bubbles is not linked to agitation of the medium before application, so that the gas bubbles can be released in unchanged form. The gas bubbles released are particularly advantageous with the help of surfactants. which may be part of the matrix, can be stabilized. Thus, in the case of the agents according to the invention, a stabilized gas bubble suspension is generally used.

Due to the high reproducibility of the vesicles generated, the risk of embolization of the lungs from blisters that are too large is minimized. In addition, the use of low molecular weight and therefore readily soluble substances for matrix formation reduces the risk of applying undissolved, particulate formulation components.

The porous matrices according to the invention are made up of a water-soluble scaffold, which generally has a molecular weight <15,000 Daltons, and a rapidly and readily water-soluble surfactant, the surfactant content in the matrix being 0.01 to 10% (m / m) . The fact that the scaffold does not necessarily have to be soluble in an organic solvent opens up a broader selection of well-tolerated scaffolders.

Possible scaffolders are:

Amino acids, polyamino acids, peptides, proteins, mono, di, tri, tetra, oligo- and polymeric saccharides, as well as their derivatives, synthetic saccharides and saccharide derivatives. Examples include L-glycine, L-alanine, L-valine, L-leucine, L-isoleucine, L-phenylalanine, L-proline, L-hydroxyproline, L-serine, L-threonine, L-tryptophan, L-asparagine , L-glutamine, L-arginine, L-histidine, glycyl-glycine, glycyl-glycyl-glycine, glucose, galactose, fructose, mannose, sorbose, sucrose, lactose, maltose, trehalose, gentiobiose, lactulose, turanose, maltotriose, melibiose , Melicose, maltotetraose, maltopentaose, stachyose, arabinose, xylose, ribose, dulcitol, xylitol, mannitol, ribitol, inositol, sorbitol, α, ß, γ- cyclodextrins,

Hydroxypropyl-β-cyclodextrin and other derivatives as well as polymeric saccharides with a molecular weight <15,000 Daltons, such as e.g. dextran 8, dextrins or synthetic saccharide polymers, e.g. Ficoll.

X-ray contrast media and contrast media for magnetic resonance imaging are also suitable as scaffold builders. Examples include iopromide, iotrolan, iopamidol, iohexol, and Gd-DTPA (gadopentetic acid), Gd-DTPA-dimeglumine salt (Magnevist), Gd-EOB-DTPA (gadoxetic acid, disodium salt) and gadobutrol. According to the invention, preference is given to renally unimpeded filterable substances with a molecular weight of <15,000 daltons (Silbernagl S., Despopoulos A., Taschenatlas der Physiologie, p. 132), saccharides with at least two sugar units, X-ray contrast agents and contrast agents being particularly suitable for magnetic resonance imaging. The use of substances with a molecular weight of <15,000 daltons gives a clear advantage over agents of the prior art, since renal elimination is ensured for such substances. Stress on the body due to the long dwell times of a contaminant component and metabolites is thus avoided. Since water solubility generally increases with decreasing molecular weight, the risk of undissolved formulation components being applied is also reduced.

Suitable surfactants are water-soluble, nonionic surfactants, those with a perfluorinated hydrocarbon building block and / or with a molecular weight of <15,000 daltons being preferred. Examples include sorbitan fatty acid esters, polyoxyethylene sorbitan, polyoxyethylene sorbitol, polyoxyethylene fatty acid esters, Glycerinpolyoxyethylenfettsäureester, ethoxylated mono-, di-, triglycerides, which if desired, may partially be hydrogenated and ethoxylated mixtures thereof, ethoxylated castor oils, ethoxylated phenols, polyoxyethylene fatty alcohol ethers, polyglycerol fatty acid ester, Sorbitanperfluorfettsäureester, Polyoxyethylensorbitanperfluorfettsäureester, Polyoxyethylensorbitolperfluorfettsäureester, Polyoxyethylene perfluoro fatty acid esters, polyoxyethylene perfluoro fatty alcohol ethers, polyglycerol perfluoro fatty acid esters, polyoxyethylene polyoxypropylene polymers and / or fluoroalkyl poly (ethylene oxide) alcohols such as, for example Zonyls *, saccharide fatty acid esters, saccharide fatty acid ethers, ethoxylated saccharide fatty acid esters, ethoxylated saccharide fatty acid ethers, fatty acid ethanolamides and / or ethoxylated fatty acid ethanolamides.

Also suitable as surfactants are phospholipids, especially hydrogenated phosphatipy Icho lin.

In addition to the gases already established in ultrasound diagnostics, such as nitrogen, oxygen, CO ₂ or air, the gases used are in particular fluorinated gases. Surprisingly, stronger and longer lasting in vivo contrast effects are observed when using the "classic" gases than are achieved with the particulate preparations of the prior art. When using fluorinated gases it is surprisingly possible to dispense with the use of gas mixtures, as are required in the preparations of the prior art.

The following are preferred according to the invention, gaseous at room temperature and normal pressure:

Tetrafluoroallenes, hexafluoro-1,3-butadiene, decafluorobutane, perfluoro-1-butenes, perfluoro-2-butenes, perfluoro-2-butyne, octafluorocyclobutane, perfluorocyclobutene, perfluorocyclopentane, perfluorodimethylamine, hexafluoroethane, tetrafluoromethane, tetrafluoromethane, tetrafluoromethane, tetrafluoromethylene Perfluoropropane and perfluoropropylene.

Among the above, the perfluorinated substances are particularly preferred.

Another aspect of the invention relates to a method for producing the matrices according to the invention. The matrices according to the invention can be produced with less effort under aseptic conditions by first providing an aqueous scaffold solution, to which gas bubble-stabilizing surfactants are added with particular advantage. The separated or combined solutions can first be sterile filtered, then the mixture thus prepared is quickly frozen. The removal of the water takes place under conditions which allow a direct transition of the ice into the gaseous state without passing through the liquid state of matter. Possible suitable conditions can be found in the phase diagram of the water (see FIG. 3). What remains is a porous matrix that is aerated with the desired gas. For complete gas exchange (i.e. to remove the residual air or water vapor contained in the pores of the matrix), repeated evacuation with subsequent pressure compensation is recommended. In order to obtain a gas phase that is as pure as possible, a vacuum of <0.1 mbar should exist immediately before the pressure equalization. The production is expediently already carried out in containers which can be closed under the desired gas phase and which can later be used directly as part of a kit.

A particular advantage of the process according to the invention is that the use of organic solvents can be dispensed with. There is also no need for technologically complex processing, as would be necessary in the case of poorly or slowly soluble or only water-dispersible substances. Residual solvent contents as a critical quality feature therefore play a role for the agents according to the invention do not matter. This is a significant advantage both from an ecological perspective and in terms of product safety. Many organic solvents, even in the smallest amounts or concentrations, are suspected of being carcinogenic and / or mutagenic.

The desired particle-free ultrasound contrast agents can easily be produced from the matrices according to the invention by adding an aqueous medium. The treating physician adds the aqueous medium immediately before use. The aqueous medium can contain the auxiliaries customary in galenics, e.g. Isotonizing and viscosity-increasing additives. It is not necessary to shake the fluidized matrix. The contrast media thus produced are distinguished by the fact that they are blood-isotonic or almost blood-isotonic. They can be injected immediately after resuspending. The concentration of the contrast media is 10 to 600 mg, preferably 50 to 400 mg of matrix material per milliliter of suspension. Depending on the application, the agents are administered in a dose of 0.01 to 0.20 ml / kg of body weight.

The agents according to the invention are for all imaging modes of sonography, such as. B. M, B, Doppler mode but also for modes in which nonlinear effects are used such as Harmony and harmony power mode equally suitable and can be produced with high reproducibility.

The bubble numbers generated from the matrix are significantly higher than those of the prior art agents, the agents therefore show significantly improved contrast effects; in particular, the time window available for the examination could be significantly extended (see also in-vivo experiments 41-52).

The following examples serve to explain the subject matter of the invention in more detail, without wishing to restrict it to them. example 1

20 g of dextran (MW: - 1200 g / mol) are mixed with 0.2 g of Zonyl ^® FSO-100 (MG: - 725 g / mol) and 80 g of water. The mixture is stirred until completely dissolved. The solution is filled with 5 g and frozen with liquid nitrogen. To

Removal of the water under conditions which allow a direct transition from the solid to the gaseous state without passing through the liquid state of matter, a gas exchange with decafluorobutane is carried out. A porous matrix remains, from which 12.3xl0 ⁹ bubbles in the range of 0.56-7.46 μm can be generated after resuspending in 10 ml of water per gram of matrix material. The number and size of bubbles was determined using a laser diffractometer from Melvern Instruments, type Master Sizer 1000.

Example 2

10 g dextran (MW: - 1200 g / mol) are mixed with 0.1 g Zonyl ^® FSO-100 (MG: - 725 g / mol) and 90 g water. The procedure is then as described in Example 1. After resuspending in 10 ml of water, 3.7xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 3

20 g of dextran 8 (MW: - 8000 g / mol) are mixed with 0.2 g Zonyl ^® FSO-100 (MW: ~ 725 g / mol) and 80 g water. The procedure is then as described in Example 1. After resuspending in 10 ml of water, 10.5xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 4

30 g of raffinose (MW: 594 g / mol) are mixed with 0.3 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 70 g water. The procedure is then as described in Example 1. After resuspending in 10 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 262 mosmol. 14.6xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance. Example 5

20 g of trehalose (MW: 342 g / mol) are mixed with 0.2 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 80 g water. The procedure is then as described in Example 1. After resuspending in 10 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 272 mosmol. 9.4 x 10 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 6

20 g of maltose (molecular weight: 342 g / mol) are mixed with 0.2 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 80 g water. The procedure is then as described in Example 1. After resuspending in 10 ml of water, a preparation is obtained which is isotonic with an osmolality of 281 mosmol. 8.2xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 7

40 g maltooligosaccharide (MW: -684 g / mol) are mixed with 0.4 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 60 g water. The procedure is then as described in Example 1. After resuspension in 10 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 314 mosmol. 30.0xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 8

20 g maltooligosaccharide (MW: -684 g / mol) are mixed with 0.2 g Zonyl ^® FSO-100 was added and 80 g of water (MG -725 g / mol). The mixture is stirred until completely dissolved. The solution is filled with 10 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspending in 10 ml of water, a preparation is obtained which is mixed with a

Osmolality of 310 mosmol is almost isotonic. 19, lxl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance. Example 9

30 g melezitose (MW: 522 g / mol) are mixed with 0.3 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 70 g water. The procedure is then as described in Example 1. After resuspending in 10 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 315 mosmol. 4.3xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 10

30 g melibiose (MW: 360 g / mol) are mixed with 0.3 g Zonyl ^® FSO-100 (MG: - 725 g / mol) and 70 g water. The mixture is stirred until completely dissolved. The solution is filled with 4 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspended in 8 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 306 mosmol. 4.3xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 11

30 g of maltotriose (MW: 504 g / mol) are mixed with 0.3 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 70 g water. The mixture is stirred until completely dissolved. The solution is filled with 3 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspended in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 296 mosmol. 3.6xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 12

30 g of Gd-EOB-DTPA (MW: 726 g / mol) (Gadoxetic acid, disodium) are mixed with 0.3 g Zonyl ^® FSO-100: - were added and 70 g of water (MW 725 g / mol). The mixture is stirred until completely dissolved. The solution is filled with 3 g and frozen with liquid nitrogen. After the water has been completely removed, one remains porous matrix. When resuspended in 10 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 344 mosmol. 24.6xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 13

30 g Gadobutrol (MW: 605 g / mol) are mixed with 0.3 g Zonyl ^® FSO-100 (MG: - 725 g / mol) and 70 g water. The mixture is stirred until completely dissolved. The solution is filled with 3 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspended in 5 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 269 mosmol. 20, lxl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 14

30 g gadopentetic acid (MW: 548 g / mol) are mixed with 0.3 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 70 g water. The mixture is stirred until completely dissolved. The solution is filled with 3 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspended in 7 ml of water, a preparation is obtained which is isotonic with an osmolality of 282 mosmol. 29, lxl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 15

30 g of Iopamidol (MW: 777 g / mol) are mixed with 0.3 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 70 g water. The mixture is stirred until completely dissolved. The solution is filled with 4 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspended in 5 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 268 mosmol. 26.3xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance. Example 16

15 g of Iopamidol (MW: 777 g / mol) are reacted with 0.15 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 85 g water. The mixture is stirred until completely dissolved. The solution is filled with 8 g each and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspended in 5 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 343 mosmol. 16.9xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 17

30 g iohexol (MW: 821 g / mol) are mixed with 0.3 g Zonyl ^® FSO-100 (MG: - 725 g / mol) and 70 g water. The procedure is then as described in Example 1. After resuspending in 5 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 264 mosmol. 24.4 × 10 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 18

20 g of iotrolan (MW 1626 g / mol) are mixed with 0.2 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 80g water. The mixture is stirred until completely dissolved. The solution is filled with 10 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspended in 3 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 256 mosmol. 10.3xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 19

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 60 g water. The procedure is then as described in Example 1. After resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 289 mosmol. 22.4xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance. Example 20

20 g iopromide (MW: 791 g / mol) are mixed with 0.2 g Zonyl ^® FSO-100 (MW: - 725 g / mol) and 80 g water. The mixture is stirred until completely dissolved. The solution is filled with 10 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 291 mosmol. 21.9xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 21

23 g Magnevist® (MW: 938 g / mol) are mixed with 0.23 g Zonyl ^® - FSO-100 (MG: -725 g / mol) and 77 g water. The mixture is stirred until completely dissolved. The solution is filled with 3 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspending in 5 ml of water, a preparation is obtained which is mixed with a

Osmolality of 342 mosmol is almost isotonic. 6, 16 × 10 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 22

40 g of iopromide (MW: 791 g / mol) are mixed with 0.4 g of ^Triton® -X-100 (MW: - 874 g / mol) and 60 g of water. The procedure is then as described in Example 1. After resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 290 mosmol. 9.56xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 23

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g of Tween ^® 20: were added and 60 g of water (MW 718 g / mol). The procedure is then as described in Example 1. After resuspending in 6 ml of water, a preparation is obtained which is mixed with a Osmolality of 289 mosmol is isotonic. 16.55xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 24

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g Cremophor ^® RH 40 (MW - 2,700 g / mol) and 60 g water. The procedure is then as described in Example 1. After resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 291 mosmol. 11.05 × 10 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 25

40 g of iopromide (MW: 791 g / mol) are mixed with 0.4 g of Rewoderm ^® Li 48-50 (MW: - 3800 g / mol) and 60 g of water. The procedure is then as described in Example 1. After resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 288 mosmol. 24.05xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 26

40 g of iopromide (MW: 791 g / mol) are mixed with 0.4 g of Solutol ^® HS 15 (MW: - 1000 g / mol) and 60 g of water. The procedure is then as described in Example 1. After resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 289 mosmol. 13.46xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 27

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g of Lutrol ^® F68 (MW - 8600 g / mol) and 60 g water. The procedure is then as described in Example 1. After resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 290 mosmol. 17.68xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance. Example 28

40 g of iopromide (MW: 791 g / mol) are mixed with 0.4 g Span ^® 85 (MW: 1028 g / mol) and 60 g of water. The procedure is then as described in Example 1. After resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 291 mosmol. 20.45xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 29

30 g iohexol (MW: 821 g / mol) are mixed with 0.3 g Zonyl ^® -FSN (MW: - 950 g / mol) and 70 g water. The procedure is then as described in Example 1. After resuspending in 5 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 269 mosmol. 23.81xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 30

30 g Gadobutrol (MW: 605 g / mol) are mixed with 0.3 g Solutol ^® HS 15 (MG: - 1000 g / mol) and 70 g water. The mixture is stirred until completely dissolved. The solution is filled with 3 g and frozen with liquid nitrogen. After the water has been completely removed, a porous matrix remains. When resuspended in 5 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 271 mosmol. 6.64xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 31

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g of Zonyl ^® - FSO-100 (MW: - 725 g / mol) and 60 g water. The procedure is then as described in Example 1. After drying, a gas exchange with hexafluoroethane is carried out. A preparation is used when resuspending in 6 ml of water obtained which is isotonic with an osmolality of 289 mosmol. 4.07xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 32

40 g of iopromide (MW: 791 g / mol) are mixed with 0.4 g of ^Triton® -X-100 (MW: 874 g / mol) and 60 g of water. The procedure is then as described in Example 1. After drying, a gas exchange with hexafluoroethane is carried out. When resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 290 mosmol. 3.01 × 10 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 33

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g of Tween ^® 20: were added and 60 g of water (MW 718 g / mol). The procedure is then as described in Example 1. After drying, a gas exchange with hexafluoroethane is carried out. When resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 289 mosmol. 4.27 × 10 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 34

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g Cremophor ^® RH 40 (MW - 2,700 g / mol) and 60 g water. The procedure is then as described in Example 1. After drying, a gas exchange with hexafluoroethane is carried out. When resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 291 mosmol. 1.76 × 10 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 35

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g Rewoderm ^® Li 48-50: are added and 60 g of water (MW -3800 g / mol). The procedure is then as described in Example 1 method. After drying, a gas exchange with hexafluoroethane is carried out. When resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 288 mosmol. 9.58xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 36

40 g of iopromide (MW: 791 g / mol) are mixed with 0.4 g of Solutol ^® HS 15 (MW: - 1000 g / mol) and 60 g of water. The procedure is then as described in Example 1. After drying, a gas exchange with hexafluoroethane is carried out. When resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 289 mosmol. 2.52 × 10 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 37

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g of Lutrol ^® F 68: were added and 60 g of water (MW -8600 g / mol). The procedure is then as described in Example 1. After drying, a gas exchange with hexafluoroethane is carried out. When resuspending in 6 ml of water, a preparation is obtained which is isotonic with an osmolality of 290 mosmol. 4.32xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 38

40 g of iopromide (MW: 791 g / mol) are mixed with 0.4 g Span ^® 85 (MW: 1028 g / mol) and 60 g of water. The procedure is then as described in Example 1.

After drying, a gas exchange with hexafluoroethane is carried out.

When resuspending in 6 ml of water, a preparation is obtained which is mixed with a

Osmolality of 291 mosmol is isotonic. 6.65xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance. Example 39

30 g iohexol (MW: 821 g / mol) are mixed with 0.3 g Zonyl ^® -FSN (MW: -950 g / mol) and 70 g water. The procedure is then as described in Example 1. After drying, a gas exchange with hexafluoroethane is carried out. When resuspended in 5 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 269 mosmol. 8.25xl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 40

30 g Gadobutrol (MW: 605 g / mol) are mixed with 0.3 g Solutol ^® HS 15 (MG: - 1000 g / mol) and 70 g water. The mixture is stirred until completely dissolved. The solution is filled with 3 g and frozen with liquid nitrogen. The procedure is then as described in Example 1. After drying, a gas exchange with hexafluoroethane is carried out. When resuspended in 5 ml of water, a preparation is obtained which is almost isotonic with an osmolality of 271 mosmol. 2, llxl0 ⁹ bubbles in the range of 0.56-7.46 μm are released per gram of substance.

Example 41

In vivo application of an agent according to the invention prepared according to Example 22:

A beagle dog [female, 11.2 kg body weight (hereinafter KGW)] is anesthetized (inhalation anesthesia approx. 2/3 oxygen, approx. 1/3 N ₂ O 1.5 - 2% enflurane; spontaneous breathing) and for a sonographic examination of the heart prepared. The examination is carried out using an HP ultrasound system (type 77020 E, 5 MHz transducer) in B mode. The test animal receives an intravenous application of the test substance (agent according to the invention produced according to Example 22). A contrast medium, which was produced analogously to WO 95/22994 (Example 12), serves as the reference substance.

The doses used are 0.1 ml / kg body weight both for the agent according to the invention and for the reference substance. The result is shown in the form of the intensity-time profiles in FIG. 4. The upper (slower falling) curve corresponds to the preparation according to the invention - as also in the following FIGS. 5-8. It can be clearly seen that the agents according to the invention show a longer lasting contrast after intravenous injection than the agents of the prior art. These contrasting properties give the doctor longer periods of time for the examination (examination window). Furthermore, the

The need for a possible subsequent injection is significantly reduced, which reduces the burden on the patient and contributes to a favorable cost / benefit ratio.

Example 42

In vivo application of an agent according to the invention prepared according to Example 27:

The procedure is as described in Example 41. A serves as the test substance

Preparation prepared as described in Example 27), an agent from WO 95/22994 (Example 12) was used as reference. The doses for reference and test substance were identical and each was 0.1 ml / kg body weight.

The intensity-time profiles are shown in FIG. 5.

Example 43

In Vivo Use of an Agent According to the Invention Manufactured According to Example 28:

The procedure is as described in Example 41, but the test animal had a body weight of 11.9 kg. A preparation prepared as described in Example 28) serves as the test substance, and an agent from EP 0365467 (Example 1) was used. The doses used were 0.05 ml / kg body weight for the agent according to the invention according to Example 28 and 0.2 ml / kg body weight for the reference. The result of the examination is shown in the form of the intensity-time profiles in FIG. 6. In this case too, despite the low dose, a more intense and longer-lasting contrast is observed for the preparation according to the invention. Example 44

In vivo application of an agent according to the invention prepared according to Example 29:

The procedure is as described in Example 43. A serves as the test substance

Preparation prepared as described in Example 29), an agent from EP 0365467 (Example 1) was used as reference.

The doses used were 0.05 ml / kg body weight for the agent according to the invention and 0.2 ml / kg body weight for the reference. The result of the examination is shown in the form of the intensity-time profiles in FIG. 7.

Example 45

In vivo application of an agent according to the invention prepared according to Example 19:

A beagle dog (female, 9.7 kg body weight) is anesthetized and the procedure described in Example 41 is followed. A preparation prepared according to Example 19 serves as the test substance, and an agent from WO 95/22994 (Example 12) was used as a reference. The doses for reference and test substance were 0.1 ml / kg body weight.

The intensity-time profiles are shown in FIG. 8.

Example 46

In vivo application of an agent according to the invention prepared according to Example 5:

The procedure is as described in Example 45. A serves as the test substance

Preparation prepared as described in Example 5), an agent from WO 95/22994 (Example 12) was used as reference. The doses for reference and test substance were identical and were 0.1 ml / kg body weight.

The result of the investigation is shown in FIG. 9. The heart of the dog was shown. In detail show:

(a) pre-contrast

(b) maximum contrast of the reference substance (c) maximum contrast of the test substance

(d) Contrast 1 minute after maximum contrast (reference)

(e) Contrast 1 minute after maximum contrast (test substance) As can be seen in the figure, the superiority of the preparations according to the invention is particularly evident when the examination is carried out over a longer period.

Example 47

In vivo application of an agent according to the invention prepared according to Example 11:

The procedure is as described in Example 41. A preparation prepared as described in Example 11) serves as the test substance, and an agent from WO 95/22994 (Example 12) was used as reference. The doses for reference and test substance were identical and were also 0.1 ml / kg body weight.

The result of the investigation is shown in FIG. 10. The meanings of numbers (a) to (e) correspond to those in Figure 9

Example 48

In vivo application of an agent according to the invention produced according to one of Examples 31, 35, 39.

A beagle dog (female, 9.6 kg body weight) is anesthetized (inhalation anesthesia approx. 2/3 oxygen, approx. 1/3 N ₂ O, 1.5 - 2% enflurane, spontaneous breathing) and prepared for a sonographic examination of the heart . The examination is carried out using an HP ultrasound system (type 77020 E, 5 MHz transducer) in B mode. The test animal each receives an intravenous application of an agent according to the invention produced according to one of Examples 31, 35, 39 and, as a reference, an injection of a contrast agent according to the prior art, which was produced analogously to WO 95/11994 (Example 12).

The doses used were 0.1 ml / kg body weight for the agents according to the invention and for the reference. The result is shown in the form of the intensity values in Table 1. It is also clearly evident here that the agents according to the invention are a show significantly higher contrast levels after intravenous injection than the reference agent.

Table 1

Example 49

In vivo application of an agent according to the invention produced according to one of Examples 4, 8, 9.

A beagle dog (female. 9.7 kg body weight) is anesthetized (inhalation anesthesia approx. 2/3 oxygen, approx. 1/3 N ₂ O, 1.5 - 2% enflurane, spontaneous breathing) and prepared for a sonographic examination of the heart . The examination is carried out using an HP ultrasound system (type 77020 E, 5 MHz transducer) in B mode. The test animal each receives an intravenous application of an agent according to the invention produced according to one of Examples 4, 8, 9 and, as a reference, an injection of a contrast agent according to the prior art, which was produced analogously to WO 95/22994 (Example 12).

The doses used were 0.1 ml / kg body weight for the agents according to the invention and for the reference. The result is shown in Table 2 in the form of the area under the intensity-time curve (density units x see). It is clearly recognizable that the Agents according to the invention show a higher area level after intravenous injection.

Table 2

Example 50

In vivo application of an agent according to the invention prepared according to one of Examples 8 and 19

A beagle dog (male, 15.5 kg body weight) is anesthetized (inhalation anesthesia 23% oxygen, 1-3% enflurane, rest nitrogen; spontaneous breathing) and prepared to derive the spectral Doppler signal from the femoral artery. The examination takes place with the ultrasonic system ATL UM-9 with the Tranducer type L 10-5. The test animal each receives an intravenous application of the test substance produced according to Example 8 or 19 and, as a reference, an application of a contrast agent produced according to WO 95/22994 (Example 12). The dose for all injections was 0.1 ml / ks body weight. The spectral duplication signal is evaluated intensitometrically and plotted against time. The resulting areas under the intensity-time curves are shown in Table 3.

Table 3

Example 51

A beagle dog (female, 9.7 kg body weight) is anesthetized (inhalation anesthesia approx. 2/3 O ₂ : approx. 1/3 N ₂ O; 1.5 - 3% enflurane, spontaneous breathing) and prepared for the perfusion examination of the kidney. The examination is carried out using an HP ultrasound system (type Sonos 1000, 5MHz) in color Doppler mode. The experimental animal receives an intravenous application of an agent according to the invention according to Example 22 (0.1 ml / kg body weight). After administration, the perfusion display of the organ is significantly improved compared to the display before application.

Example 52

A beagle dog (female, 9.7 kg body weight) is anesthetized (inhalation anesthesia approx. 2/3 O ₂ ; approx. 1/3 N ₂ O; 1, 5 - 3% enflurane, spontaneous breathing) and for sonographic examination of the abdominal aorta prepared. The examination is carried out with an ultrasound system of the brand ATL type UM9 with transducer C10-5 in harmony B- Fashion. The experimental animal receives an intravenous application of an agent according to the invention prepared according to Example 8 (dose 0.1 ml / kg body weight). Immediately after the end of the injection, the vascular volume is marked echogenically. Before the injection, the volume was without enhancement.

Example 53

40 g iopromide (MW: 791 g / mol) are mixed with 0.4 g of ethoxylated fatty acid monoethanolamide (Aminol N ^®, MW: 480 g / mol) and 60 g water. The procedure is then as described in Example 1. After resuspending in 6 ml of water, an isotonic preparation is obtained. 20.34 x IO ⁹ bubbles are released in the contrast-relevant range of 0.56-7.46 μm per gram of substance.

Example 54

0.67 g of sucrose palmitate stearate 7 are mixed with 100 g of water and heated in the micro wave. After cooling, a slightly cloudy, stable solution is obtained. 60 g of this opalescent solution are mixed with 40 g iopromide (MW: 791 g / mol). The procedure is then as described in Example 1. After resuspending in 6 ml of water, an isotonic preparation is obtained. 62.01 x IO ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance.

Example 55

40 g of iopromide (MW: 791 g / mol) are mixed with 60 g of a sucrose palmitate stearate 15 solution (w = 0.67%). The procedure is then as described in Example 1. After resuspending in 6 ml of water, an isotonic preparation is obtained. 38.97 x 10 ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance. Example 56

0.67 g of sucrose palmitate stearate 7 are mixed with 100 g of water and heated in the microwave. After cooling, a slightly cloudy, stable solution is obtained. 60 g of this opalescent solution are mixed with 40 g iopromide (MG.-791 g / mol). The procedure is then as described in Example 1. The gas exchange takes place with perfluorohexane. After resuspending in 6 ml of water, an isotonic preparation is obtained. 2.82 x IO ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance.

Example 57

0.67 g of sucrose palmitate stearate 7 are mixed with 100 g of water and heated in the microwave. After cooling, a slightly cloudy, stable solution is obtained. 60 g of this opalescent solution are mixed with 40 g iopromide (MW: 791 g / mol). The mixture is stirred until completely dissolved. The entire solution is frozen by dropping it in liquid decafluorobutane. After removal of the water under conditions which allow a direct transition from the solid to the gaseous state without the liquid state being passed through, the product is filled with 1 g and a gas exchange is carried out with decafluorobutane. After resuspending in 3 ml of water, an isotonic preparation is obtained. 34.07 x IO ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance.

Example 58

0.4 g of hydrogenated phosphatipylcholine (Pro Lipo H ^® ) are mixed with 60 g of water and then with 0.4 g of iopromide (MW: 791 g / mol). The procedure below is as described in Example 1. After resuspending in 6 ml of water, an isotonic preparation is obtained. 27.97 x 10 ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance. Example 59

0.4 g of hydrogenated, oil-free soy lecithin (Epikuron 100H ^® ) are mixed with 60 g of water and then with 0.4 g of iopromide (MW: 791 g / mol). The procedure below is as described in Example 1. After resuspending in 6 ml of water, an isotonic preparation is obtained. 52.97 x 10 ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance.

Example 60

1.5 g of sucrose palmitate stearate 7 are mixed with 100 g of water and heated in the microwave. After cooling, a slightly cloudy, stable solution is obtained. 70 g of this opalescent solution are mixed with 30 g maltooligosaccharide (MW: 684 g / mol) and 0.1 g PVA (MG: 10000 g / mol). The preparation is filled at 4 g. The procedure is then as described in Example 1. After resuspending in 6 ml of water, an isotonic preparation is obtained. 9.37 x IO ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance.

Example 61

0.6 g of hydrogenated Phosphatipylcholin (Pro Lipo H ^®) then with 70 g water and 30 g maltooligosaccharide: offset (MW 684 g / mol). The preparation is filled at 4 g. The procedure below is as described in Example 1.

After resuspending in 6 ml of water, an isotonic preparation is obtained. Per

21.08 x IO ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released.

Example 62

40 g iopromide (MW: 791 g / mol) are mixed with 0.04 g of polyoxyethylene sorbitan monolaurate Tween 21 ^®) and 60 g of water. The mixture is stirred until completely dissolved. The preparation is filled with 5 g and frozen in liquid propane. After removal of the water under conditions that allow a direct transition from the solid to the gaseous state without the liquid If the physical state is exceeded, a gas exchange with decafluorobutane is carried out. After resuspending in 6 ml of water, an isotonic preparation is obtained. 3.77 x IO ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance.

Example 63

0.67 g of sucrose palmitate stearate 7 are mixed with 100 g of water and heated in the microwave. After cooling, a slightly cloudy, stable solution is obtained. 60 g of this opalescent solution are mixed with 40 g iopromide (MW: 791 g / mol). The preparation is filled with 5 g and frozen in liquid butane. After removal of the water under conditions which enable a direct transition from the solid to the gaseous state without passing through the liquid state of matter, a gas exchange with decafluorobutane is carried out. After resuspending in 6 ml of water, an isotonic preparation is obtained. 34.16 x IO ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance.

Example 64

40 g of iopromide (MW: 791 g / mol) are mixed with water until completely dissolved. 0.4 g of hydrogenated phosphatidylcholine from soy (Epikuron 200SH) are mixed with tertiary butanol until completely dissolved. The solutions are combined and filled up with water to a total weight of 100g. The procedure is then as described in Example 1. After resuspending in 6 ml of water, an isotonic preparation is obtained. 15.95 x IO ⁹ bubbles in the contrast-relevant range of 0.56-7.46 μm are released per gram of substance.

Example 65

20 g of stachyose (MW: 739 g / mol) are mixed with 0.4 g of hydrogenated phosphatidylcholine (Pro Lipo H ^® ) and 80 g of water. The preparation is filled at 2.5 g each.

The procedure is then as described in Example 1. After resuspending in 2.5 ml of water, an isotonic preparation is obtained. Example 66

A beagle dog (female, 11.8 kg body weight) is anesthetized (inhalation anesthesia 23% oxygen. 1 - 3% enflurane. Rest nitrogen);

Spontaneous breathing) and prepared to derive the spectral Doppler signal from the femoral artery. The examination is carried out with the ultrasonic system ATL UM-9 with the transducer type L 10-5. The test animal each receives an intravenous application of the test substance prepared according to Example 54 (0.05 ml / kg) and, as a reference, an application of a contrast agent prepared according to EP 0 365 467 (Example 1, 0.2 ml / kg). FIG. 11 shows the intensity-time profiles of the two injections. The clearly more intense and longer lasting contrast of the preparation according to the invention is clearly recognizable.

Example 67

A beagle dog (female, 11.9 kg body weight) is anesthetized (inhalation anesthesia 23% oxygen, 1 - 3% enflurane, rest nitrogen; spontaneous breathing) and prepared to derive the spectral Doppler signal from the femoral artery. The examination is carried out with the ultrasound system ATL UM-9 with the transducer type L 10-5. The test animal each receives an intravenous application of the test substance produced according to Example 58 (0.05 ml / kg) and, as a reference, an application of a contrast agent produced according to EP 0365467 (Example 1, 0.2 ml / kg). Figure 12 shows the intensity-time profiles of the two injections. The clearly more intense and longer lasting contrast of the preparation according to the invention is clearly recognizable.

Example 68

A beagle dog (female, 12.1 kg body weight) is anesthetized (inhalation anesthesia 23% oxygen, 1 - 3% enflurane, remainder nitrogen; spontaneous breathing) and prepared to derive the spectral Doppler signal from the femoral artery. The examination is carried out with the ultrasound system ATL UM-9 with the transducer type L 10-5. The test animal each receives an intravenous application of the test substance produced according to Example 59 (0.05 ml / kg) and, as a reference, an application of a contrast agent produced according to EP 0365467 (example 1, 0.2 ml / kg). The area under the intensity-time curve is 252.2% of the reference.

Example 69

A beagle dog (female, 12.1 kg body weight) is anesthetized (inhalation anesthesia 23% oxygen, 1 - 3% enflurane, remainder nitrogen; spontaneous breathing) and prepared to derive the spectral Doppler signal from the femoral artery. The examination is carried out with the ultrasound system ATL UM-9 with the transducer type L 10-5. The test animal each receives an intravenous application of the test substance produced according to Example 64 (0.05 ml / kg) and, as a reference, an application of a contrast agent produced according to EP 0365467 (Example 1, 0.2 ml / kg). The area under the intensity-time curve is 223.8% of the reference.

Example 70

A beagle dog (male, 17.1 kg body weight) is anesthetized (inhalation anesthesia 23% oxygen, 1 - 3% enflurane, rest nitrogen; spontaneous breathing) and prepared to derive the spectral Doppler signal from the femoral artery. The examination is carried out with the ultrasound system ATL UM-9 with the transducer type L 10-5. The test animal each receives an intravenous application of the test substance produced according to Example 65 (0.05 ml / kg) and, as a reference, an application of a contrast agent produced according to EP 0 365 467 (Example 1, 0.2 ml / kg). The area under the intensity-time curve is 181.0% of the reference.

Claims

claims

1. Preparations for the preparation of a preparation for ultrasound diagnostics, consisting of a porous, solid, water-soluble matrix containing a low molecular weight scaffold, a surfactant and a gas, the gas being enclosed in the pores of the matrix.

2. Porous matrix according to claim 1 containing as a scaffold a water-soluble scaffold with a molecular weight <15,000 daltons from the group of amino acids, polyamino acids, peptides, proteins, mono-,

Di-, tri-, tetra-, oligo- and polymeric saccharides, as well as their derivatives, synthetic saccharides and their derivatives.

3. Porous matrix according to claim 1 or 2, containing L-glycine, L-alanine, L-valine, L-leucine, L-isoleucine, L-phenylalanine, L-proline, L- as a scaffold.

Hydroxyproline, L-serine, L-threonine, L-tryptophan, L-asparagine, L-glutamine, L-arginine, L-histidine, glycyl-glycine, glycyl-glycyl-glycine, glucose, galactose, fructose, mannose, sorbose, Sucrose, lactose, maltose, trehalose, gentiobiose, lactulose, turanose, maltotriose, melibiose, melicose, maltotetraose, maltopentaose, stachyose, arabinose, xylose,

Ribose, dulcitol, xylitol, mannitol, ribitol, inositol, sorbitol, α, β, γ-cyclodextrins, hydroxypropyl-β-cyclodextrin, dextran 8, dextrins and / or Ficoll.

4. Porous matrix according to claim 1 or 2 containing as a scaffold

X-ray contrast media or contrast media for magnetic resonance imaging.

5. Porous matrix according to claim 4 containing as a scaffold iopromide, iotrolan, lopamidol and / or iohexol.

6. Porous matrix according to claim 4 containing as a scaffold Gd-DTPA (gadopentetic acid), Gd-DTPA-dimeglumin salt (Magnevist), Gd-EOB-DTPA (gadoxetic acid, disodium salt) and / or gadobutrol.

7. Porous matrix according to one of claims 1 to 6 containing as a surfactant a water-soluble, nonionic surfactant, the surfactant content in the matrix being 0.01 to 10% (m / m).

8. Porous matrix according to one of claims 1 to 7 containing as a surfactant sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene fatty acid esters, glycerol polyoxyethylene fatty acid esters, ethoxylated mono-, di-, triglycerides, which, if desired, can be partially hydrogenated and ethoxylated

Mixtures of these, ethoxylated castor oils, ethoxylated phenols, polyoxyethylene fatty alcohol ethers, polyglycerol fatty acid esters, sorbitan perfluoride fatty acid esters, polyoxyethylene sorbitan perfluoride fatty acid esters, polyoxyethylene sorbitol perfluoride fatty acid esters, polyoxyethylene perfluoride fatty acid esters, ethoxylated castor oils,

Polyoxyethylene perfluorinated fatty alcohol ethers, polyglycerol perfluorinated fatty acid esters, polyoxyethylene polyoxypropylene polymers, fluoroalkyl poly (ethylene oxide) alcohols, saccharide fatty acid esters, saccharide fatty acid ethers, ethoxylated saccharide fatty acid esters, ethoxylated saccharide fatty acid ethers, fatty acid ethanolamides and / or ethoxylated fatty acid ethanolamides.

9. Porous matrix according to one of claims 1 to 7 containing as surfactant phospholipids.

10. Porous matrix according to one of claims 1 to 9 containing as a surfactant

Surfactant with a perfluorinated hydrocarbon building block and / or with a molecular weight <15,000 Daltons.

11. Porous matrix according to claim 1 to 10 containing as gas nitrogen, oxygen, CO ₂ , air and fluorinated gaseous compounds.

12. Porous matrix according to claim 1 to 11 containing as a gas tetrafluoroallene, hexafluoro-l, 3-butadiene, decafluorobutane, perfluoro-1-butenes, perfluoro-2-butenes, perfluoro-2-butyne, octafluorocyclobutane, perfluorocyclobutene, perfluorocyclopentane, perfluorodimethylamine Hexafluoroethane,

Tetrafluorethylene, pentafluorothio (trifluor) methane, tetrafluoromethane, perfluoropropane and / or perfluoropropylene.

13. Porous matrix according to claim 1 to 12 containing as gas a perfluorinated substance.

14. Ultrasound contrast medium generated from a porous matrix according to one of claims 1 to 13 containing as a liquid carrier medium, water optionally with the additives customary in pharmaceutical technology.

15. Ultrasound contrast medium according to claim 14 containing as a carrier medium physiological electrolyte solution, an aqueous solution of mono- or polyhydric alcohols or an aqueous solution of a mono- or disaccharide.

16. A kit for the production of an ultrasound contrast agent containing gas bubbles consisting of

a) a first container provided with a closure which enables the removal of the content under sterile conditions and is filled with the liquid suspension medium and

b) a second container provided with a closure which allows the addition of the suspension medium under sterile conditions, filled with the porous matrix according to one of claims 1 to 13 and a gas, the volume of the second container being dimensioned such that the suspension medium of the first container completely in the second

Container finds place.

17. A process for the production of porous matrices according to one of claims 1 to 13, characterized in that first an aqueous solution of the desired scaffolding agent is prepared, to which gas bubble stabilizing surfactants are optionally added, then the solution thus produced is freeze-dried, after drying the porous matrix is aerated with the desired gas.