Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Molecular bilayer structure
Reexamination Certificate
1998-04-10
2003-11-11
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Molecular bilayer structure
C424S001110, C514S938000
Reexamination Certificate
active
06645463
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to an oil-in-water emulsion, and more particularly, to an oil-in-water emulsion that functions as a blood-pool selective carrier or delivery vehicle for lipophilic imaging agents, or lipid-soluble derivatives of water- soluble, imaging agents incorporated therein.
Conventional water-soluble contrast media for x-ray computed tomography (CT) and magnetic resonance imaging (MRI) rapidly diffuse out of the blood following injection. Vascular imaging, for example, therefore depends on invasive intra-arterial infusion of large amounts of contrast media at or near the suspected site of disease. Despite administration of a bolus dose of contrast media, enhancement lasts for only a few seconds. In CT angiography, as a specific example, a large amount (<200 ml) of a conventional water-soluble urographic agent is administered directly into the artery at a rate approaching 5 ml/sec. Such rapid administration can cause nausea and vomiting. Because conventional urographic agents are rapidly distributed throughout the vascular space before rapid renal elimination, CT scanning must be accomplished within 30 seconds of administration while the agent is still in the circulation phase. Intravascular contrast is rapidly lost as the agent diffuses into the extravascular space and distributes nonspecifically throughout the body. There is, therefore, a need for a delivery vehicle for CT scanning that can be administered less invasively and that will prolong the presence of the agent in the blood.
Several experimental CT agents have been developed to provide extended circulation time in the blood, including high molecular weight carboxymethyl dextrans and nanocrystalline particulates. Iodinated versions of the dextrans have opacified blood for up to 20 minutes, however, significantly delayed clearance (greater than a day) from the liver poses a concern. The nanocrystalline particulates comprising, in one example, solid ethyl diatrizoate having a particle size ranging from 200-400 nm, are also very slowly cleared by the reticuloendothelial system (RES) of the liver and spleen. There is, thus, a need for a delivery vehicle that will circulate in the blood for a prolonged period of time, but which will be metabolized and cleared from the system within an acceptable time period.
In addition to the foregoing experimental agents, several liposomal oil-in-water emulsions have been developed wherein the inclusion of polyethylene glycol (PEG) or a PEG derivative of a phospholipid, was found to reduce RES uptake and clearance of active agent from parenterally administered delivery active agent and to prolong the blood half life of the vehicles. Although liposomes and lipoproteins share some common structural lipid components and have considerable overlap in particle size, there remain significant differences in particle structure and in the mechanism of sequestration of the two particle types by their respective target tissues.
Liposomes, which are artificially prepared lipid vesicles formed by single or multiple polar lipid bilayers, consisting primarily of phospholipids and cholesterol, enclosing aqueous compartments are particulate in nature, and hence, have potential for delivering agents contained therein to the RES. Investigators have attempted to load liposomes with both ionic and non-ionic water-soluble urographic contrast media. However, stabilization of the resulting liposome against loss of contrast media from the bilayers has proven to be a major problem. Moreover, incorporation of neutral lipophilic agents into the bilayer is limited by the low capacity of the lipophilic agents to become incorporated in the membrane matrix and the restricted loading capacity of the liposome.
Lipoproteins, on the other hand, are naturally-occurring, oil-in-water emulsions composed of a monolayer of polar (amphiphilic) lipids that surround a neutral lipid core made up of cholesteryl esters and triglycerides. A variety of apolipoproteins associate with the polar monolayer of these lipid-transport particles. Each of the apolipoproteins plays a role as a recognition factor for tissue-selective, receptor-mediated uptake or in enzyme-mediated metabolism of the various classes of lipoproteins. Liposomes, which lack these specific surface recognition proteins, are rapidly sequestered by macrophages of the RES in the lungs, liver (Kupffer cells), spleen, and bone marrow. Liposomal biodistribution can be modulated somewhat by alteration of the surface charge, particle size, and chemical modification of surface components, although a significant portion of the modified liposomal material is still sequestered by the macrophages. A problem with RES-mediated particulates, such as the aforementioned liposomes is toxicity. Large imaging doses of particulate contrast agents have been associated with engorgement of the Kupffer cells of the liver resulting in sinusoidal congestion and consequent activation of macrophages which release toxic mediators.
Accordingly, there remains a great need in the art for less toxic delivery vehicles or compositions, including contrast-producing oil-in-water emulsions for diagnostic purposes that have prolonged blood circulation time, yet are cleared from the system within a reasonable period of time.
It is, therefore, an object of this invention to provide a delivery vehicle, specifically a blood-pool selective, surface-modified, oil-in-water emulsion, for transport of lipophilic agents, or lipophilic derivatives of water soluble agents, such as radiologic contrast agents.
It is another object of the invention to provide a blood-pool selective delivery vehicle, specifically a lipoprotein-like oil-in-water emulsion, that achieves prolonged retention in the circulation by avoiding sequestration by the RES.
It is still another object of this invention to provide a blood-pool selective delivery vehicle that is substantially free of liposomal contamination.
It is also an object of this invention to provide a delivery vehicle, specifically a blood-pool selective, surface-modified, oil-in-water emulsion, that remains in the blood for a prolonged period of time (on the order of 1 to 2 hours versus seconds) following intravenous administration (versus invasive arterial catheterization).
SUMMARY OF THE INVENTION
The foregoing and other objects are achieved by this invention which is a surface-modified synthetic oil-in-water lipid emulsion, resembling endogenous lipoproteins, in order to take advantage of the natural lipid transport system of a living being. The surface-modified oil-in-water emulsion of the present invention have been modified with derivatized polyethylene glycol or polyethylene glycol derivatives of phospholipids to prolong retention time in the blood, possibly by interfering with the association of the emulsion particles with apolipoproteins and/or opsonins which are responsible for mediating cellular uptake and circulatory elimination of the vehicle. Lipophilic agents or lipophilic derivatives of water-soluble agents which are diagnostically, therapeutically, or biologically active or inactive, inserted into the lipid core of the emulsion are retained in the blood.
In accordance with the present invention, the mean oil phase particle size is between 50 and 150 nm (number weighted), with a narrow size distribution (50 to 250 nm) wherein no more than 2% of the particles have a diameter that falls outside of the range (i.e., being greater than 250 nm). The emulsion should have no detectable particles with a diameter greater than 1 &mgr;m. Moreover, the emulsion should not be contaminated with liposomes.
In a composition aspect of the invention, the synthetic oil-in-water emulsion of the present invention has the general formula:
1. up to 50% lipophilic core components (w/v);
2. up to 10% emulsifier (w/v);
3. up to 5% cholesterol (w/v);
4. up to 5% derivitized PEG or PEG-derivative of a phospholipid (w/v):
5. up to 5% osmolality adjusting agent (w/v);
6. optionally, up to 1% antioxidant (w/v); and
7. water to final volume.
The typ
Counsell Raymond E.
Longino Marc A.
Weichert Jamey P.
Jones Dameron L.
Monsano Raphael A.
Rohm Benita J.
The Board of Regents of the University of Michigan
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