Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Patent
1993-12-07
1995-08-29
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
4241951, 514938, 514943, A61K 4904
Patent
active
054458110
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE92/00261 filed Apr. 22, 1992.
The present invention is related an emulsion intended essentially for intravenous administration as a contrast agent for visibilizing the presence of tumours, metastases and the like in the liver and spleen of a patient. The emulsion is characterized in that it contains a lipophilic iodized and/or bromated substance which is emulsified as an oil-in-water emulsion with the aid of emulsifiers, for instance mixtures of phospholipids and derivatives of cyclopenta-phenanthrene (steroids), in particular sterols. The emulsion can be autoclaved, is highly stable and has a mean parfide size of smaller than 1 .mu.m. This contrast agent is characterized by its very high affinity to liver and spleen, this affinity being about three times greater than the affinity of earlier known contrast emulsions of the same particle size.
The addition of steroids, and then particularly the addition of phytosterols or cholesterol to the oil phase of iodized or bromated organic substances in emulsion form in accordance with this patent application enables the particles in the emulsion to be directed specifically to liver and spleen, subsequent to being administered intravenously. The inventive emulsion therewith fulfils all the requirements that can be placed on an organ specific contrast agent intended for computed tomography.
INTRODUCTION
Various emulsions containing iodized fat have earlier been produced for use as a contrast agent. These iodine-containing fat emulsions have been found to afford advantages that are not afforded with water-soluble X-ray contrast media. For instance, the iodine-containing fat emulsions are characterized by a low osmotic pressure, among other things. This is particularly benefidal in the case of intravenous administration, since it reduces injury to the endothelial tissue and also reduces the occurrence of thrombophlebitis.
Iodine-containing fat emulsions have been the subject of particular interest, because the emulsion particles were taken-up into the cells of the reticuloendothelial system (RES-cells). This observation was made as early as 1930, by W. S. Keith, D. R. Brigys (Proc. Soc. Exp. Biol. Med. 27: 538, 1930). This enabled liver and spleen with large quantities of RES-cells to be made more radio-opaque than other tissues. However, it is only recently that it has been possible to utilize this property of the iodine-containing emulsions, due to the development of more sensitive methods of X-ray examination utilizing so-called computed tomography. This has made it possible to improve radiological examinations on the liver, for instance, so that small tumours, metastases, abscesses, etc. in the liver can be observed more readily. One reason for this is that the RES-cells in the liver which take-up the emulsion droplets are not found in tumour tissue. Consequently, because the tumours do not take-up the contrast agent, they are seen as "voids" in the image obtained with computed tomography. Because of the improved X-ray diagnosis made possible in this way, different methods of producing iodine-containing fat emulsions for intravenous injection have been investigated intensely over recent years.
A Summary is given in the following of earlier publications, patent specifications and patent applications which relate to iodine-containing fat emulsions for intravenous use and intended particularly for X-ray examination of liver and spleen.
1. Roth, Stephan. "Rontgenkontrastmittel auf der Basis einer Emulsion von jodierten olen". Patent Specification DE 26.02.907 (27.1.76). The invention relates to an emulsion (oil-in-water) which contains iodized triglyceride. The emulsion is characterized in that it contains 50-60% of an iodized triglyceride and 2-10% of polyoxyethylene-sorbitan fatty add esters as emulsifier. The resultant emulsion can only be sterilized by gamma radiation. The emulsion is intended for use with lymphangiography and hepatosplenography.
2. Grimes, George and associates. "Formulation and Evaluation of Ethiodized Oil Em
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Norrlind Bjorn
Wretlind Arvid
Hollinden Gary E.
Pharmacia AB
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