Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1997-05-29
2000-04-04
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
424 121, 424 9321, 424 951, 424 93, 424 9361, 424 942, A61K 9127
Patent
active
060458216
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel liposomal agents, in particular parenterally administrable agents having membrane bound macrocyclic chelant groups which carry diagnostically or therapeutically useful metal ions. Such liposomal agents may be used in therapy or as contrast enhancing agents in diagnostic imaging modalities such as MRI, scintigraphy, X-ray and CT.
The use of diagnostic agents in medical imaging procedures is well established.
In MRI, contrast agents generally derive their contrast enhancing effect from the inclusion of a material exhibiting paramagnetic, ferrimagnetic, ferromagnetic or superparamagnetic behaviour, eg. a chelated paramagnetic metal ion (such as Gd or Dy) or an iron oxide nanoparticle. These materials affect the characteristic relaxation times of the imaging nuclei in the body regions into which they distribute causing an increase or decrease in MR signal intensity.
In X-ray and CT, contrast agents derive their effect from their ability to alter the X-ray transmission characteristics of the body regions into which they distribute and as a result the use of chelated heavy metal ions, which have large X-ray cross sections, as X-ray contrast agents has been proposed.
In scintigraphy, the imaging agent is a radionuclide, eg. a chelated radioactive metal ion, generally a gamma emitter.
For therapy, the use of chelated metal species, either radionuclides or metals which themselves have a therapeutic effect, such as vanadium for diabetes therapy, is also well known.
While therapeutically and diagnostically useful metal chelates have long been used in medicine, there does remain a need for metal chelate based agents with improved biodistribution and bioelimination profiles. On parenteral administration, simple water soluble low molecular weight metal chelates, such as the MRI contrast agents GdDTPA and GdDTPA-BMA, distribute throughout the extracellular fluid (ECF) without any particular site specificity and are rapidly excreted through the kidneys by glomerular filtration. Other agents have been proposed which, due to their particulate or lipophilic nature are rapidly abstracted from the blood by the reticuloendothelial (RES) system or by liver hepatocytes and thus are suitable as hepatobiliary agents.
One approach to the development of a blood pool agent, ie. an agent which remains within the vascular space for an extended period sufficient to expand the time available for imaging, has been to use water-soluble polychelate macromolecules with molecular weights above the kidney threshold. Another approach in the effort to develop site-specific agents has been to couple chelates, eg. monochelates, oligochelates or polychelates, to a site directed molecule, usually a macromolecule. Thus for example gadolinium chelates have been coupled to albumin and immunoglobulins. There are however several drawbacks to this approach. A large number of chelated metal ions per macrostructure is required. Where a large number of chelates are coupled to a site-directed molecule, its site-specificity may be reduced. Controlling the preparation processes to give reproducible metal loading levels, homogeneous products and high target specificity is difficult and such processes are costly. The excretion and metabolic pathways for such agents are complex and not well understood. The scientific study and documentation required to trace all potential metabolites produced by RES elimination would be extensive. It is thus not surprising that, to date, there are no macromolecular gadolinium based contrast agents in clinical trials.
Since injected particulates are rapidly taken up by the RES, the use of liposomal contrast agents has also been widely suggested.
Liposomes, the term is used herein to refer to particles having one or more encapsulating membranes formed by amphiphilic molecules (such as lipids for example) and in particular particles having a bilayer membrane and an enclosed aqueous core, are versatile carriers for the site specific delivery of therapeutic and diagnostic agents. They can be used to selec
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Garrity Martha
Varadarajan John
Watson Alan David
Kishore Gollamudi S.
Nycomed Salutar Inc.
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