Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Patent
1993-12-30
1996-08-27
Prescott, Arthur C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
424 9455, 424 945, 436508, A61K 4904, C07F 910
Patent
active
055502636
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention is related to a phospholipid-based compound comprising an X-ray contrast-giving moiety, which compound in the form of liposomes in an aqueous formulation after intravenous administration can be used for X-ray examination of the reticuloendothelial system (RES), especially the liver.
BACKGROUND
There is in medicine a great need for a non-toxic contrast agent for the liver. In the liver, as well as in the spleen which are part of the reticuloendothelial system, there are so called Kupffer cells, the normal task of which is to clear the blood of foreign particles. It is a well known fact that colloidal particles, such as liposomes, when injected into the body, are concentrated in said Kupffer cells. In a number of diseases, such as cancer, there are, however, no such cells in the disordered tissue. By using a particulate contrast agent, which will only be taken up by the healthy tissue, there is therefore a possibility to differentiate between disordered and healthy tissue.
In order to replace Thorotrast, which was introduced in 1929 and abandoned due to the development of histological changes, many attemps have been made to find a contrast agent for the liver not being toxic. All these experiments have in common that the results often were diagnostically satisfactory but nevertheless discouraging as all efforts lead to unavoidable toxicity. A number of particulate contrast agents has been developed and tested which have been based on polymeric materials or on lipids combined with a contrast giving substance. Said contrast agents have been of different types such as iodinated compounds for use in X-ray diagnostics, conventional as well as for computed tomography (CT), magnetic materials for use in magnetic resonance imaging (MRI) and radioactive isotopes.
For toxicological reasons, that is for avoiding the risk of radiation as well as of introducing foreign substances, it should be of advantage to use a conventional X-ray contrast agent of the type iodinated carboxylic acid which is well known and highly compatible with the human body.
As there are only about 1% Kupffer cells in the liver, the contrast-giving moiety of the contrast agent must not be too small; it has been concluded that in general the contrast-giving moiety should not be less than about 25% w/w for an uptake to be diagnostically detectable. In addition the size of the particles should be within the interval 0.05-5 .mu.m as larger particles to a great extent are caught in the lungs and smaller particles will not be taken up by the Kupffer cells.
Another problem with a particulate contrast agent to be used for parenteral administration, and intravenous administration in particular, is the demand for sterilization. When a contrast agent is to be prepared on a large scale for a medical application, one of the most important steps in the manufacturing process is the sterilization. In order to remove small viruses and pathogenetic materials heat sterilization is still the only reliable method. The particle structure of many of the previously known particulate carriers for contrast agents, such as liposomes and starch-based particles, can generally not withstand this treatment.
PRIOR ART
Particulate contrast agents based on lipids can be divided into two main categories. On the one hand an appropriate contrast agent can be included in a carrier particle, for instance a liposome, and on the other hand the contrast agent can be linked to a lipid as such, and subsequently by means of excipients be formed to particles, such as liposomes or emulsion droplets. In this context liposome refers to a spherical particle comprising two or more bilayers of mainly phospholipids, in the interspace of which hydrophilic substances, for instance water, can be included. Emulsion refers to drops of lipid, mainly consisting of triglycerides which have been stabilised preferably with phospholipids, in an aqueous continuous phase.
Different methods have been tested in the preparation of lipid systems based on emulsions. Lipoida
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Bengmark Stig
Hersl of Bengt
Larsson K.ang.re
Karlshamns LipidTeknik AB
Prescott Arthur C.
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