Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
1997-11-20
2002-04-23
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S001110, C424S001650, C424S009100, C424S009300, C424S450000, C546S011000, C544S001000, C540S001000, C540S145000
Reexamination Certificate
active
06375930
ABSTRACT:
BACKGROUND OF THE INVENTION
A drug delivery system should deliver drug at a rate dictated by the needs of a medical procedure over the period of the procedure, that is, the goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to promptly achieve, and then maintain, the desired drug concentration. This objective emphasizes the need for spatial placement and temporal delivery of a drug or treatment. Spatial placement is the targeting of a drug to a specific organ, tissue, or bodily system such as the blood stream; while temporal delivery refers to controlling the rate of drug delivery to the target.
Targeted drug delivery systems include colloidal drug delivery systems and resealed or modified cells, for example, resealed or modified erythrocytes or leukocytes. Colloidal drug delivery systems include nanoparticles, microcapsules, nanocapsules, macromolecular complexes, polymeric beads, microspheres, liposomes, and lipid vesicles.
Liposomes are formed from phospholipids that are dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (also termed multilamellar vesicles (MLVs)). MLVs generally have diameters of from 4 mm to 25 nm. Sonication or solvent dilution of MLVs results in the formation of small unilamellar vesicles (SUVs) with diameters in the range of 300 to 500 Å.
Liposomes resemble cellular membranes, and water- or lipid-soluble substances can be entrapped in the aqueous spaces or within the bilayer, respectively. An important determinant in entrapping compounds is the physicochemical properties of the compound itself. Polar compounds are trapped in the aqueous spaces and are released through permeation or when the bilayer is broken; nonpolar compounds bind to the lipid bilayer of the vesicle, and tend to remain there unless the bilayer is disrupted by temperature or exposure to lipoproteins.
Liposomes may interact with cells via a number of different mechanisms, for example: endocytosis by phagocytic cells of the reticuloendothelial system such as macrophages and neutrophils; adsorption to the cell surface, either by nonspecific weak hydrophobic or electrostatic forces, or by specific interactions with cell-surface components; fusion with the plasma cell membrane by insertion of the lipid bilayer of the liposome into the plasma membrane, with simultaneous release of liposomal contents into the cytoplasm; or by transfer of liposomal lipids to cellular or subcellular membranes, or vice versa, without any association of the liposome contents. It often is difficult to determine which mechanism is operative and more than one may operate at the same time.
Intravenously injected liposomes may persist in tissues for hours or days, depending on their composition, and half-lives in the blood range from minutes to several hours. Larger liposomes are taken up rapidly by phagocytic cells of the reticuloendothelial system and exit only in places where large openings or pores exist in the capillary endothelium, such as the sinusoids of the liver or spleen. Thus, these organs are the predominant site of uptake. On the other hand, smaller liposomes show a broader tissue distribution but still are sequestered highly in the liver and spleen. In general, this in vivo behavior limits the potential targeting of liposomes to only those organs and tissues accessible to their large size. These include the blood, liver, spleen, bone marrow and lymphoid organs.
Attempts to overcome the limitation on targeting of liposomes have centered around two approaches. One is the use of antibodies, bound to the liposome surface, to direct the antibody and the liposome contents to specific antigenic receptors located on a particular cell-type surface. Further, carbohydrate determinants (glycoprotein or glycolipid cell-surface components that play a role in cell-cell recognition, interaction and adhesion) may also be used as recognition sites since they have potential in directing liposomes to particular cell types.
Further lipid vesicles, such as nonphospholipid paucilamellar lipid vesicles (PLV's), are made from materials such as polyoxyethylene fatty esters, polyoxyethylene fatty acid ethers, diethanolamines, long-chain acyl amino acid amides, long-chain acyl amides, polyoxyethylene sorbitan mono and tristearates and oleates, polyoxyethylene glyceryl monostearates and monooleates, and glyceryl monostearates and monooleates, (U.S. Pat. Nos. 4,911,928, 4,917,951, and 5,000,960).
Resealed erythrocytes are another form of targeted drug delivery. When erythrocytes are suspended in a hypotonic medium, they swell to about one and a half times their normal size, and the membrane weakens, resulting in the formation of small pores. The pores allow equilibration of the intracellular and extracellular solutions. If the ionic strength of the medium then is adjusted to isotonicity, the pores will close and cause the membrane of the erythrocyte to return to normal or “reseal”. Using this technique with a drug present in the extracellular solution, it is possible to entrap a substantial amount of the drug inside the resealed erythrocyte and to use this system for targeted delivery via intravenous injection.
Studies on the behavior of normal and modified reinfused erythrocytes indicate that, in general, normal aging erythrocytes, slightly damaged erythrocytes and those coated lightly with antibodies are sequestered in the spleen after intravenous reinfusion; but heavily damaged or modified erythrocytes are removed from the circulation by the liver. This suggests that resealed erythrocytes can be targeted selectively to either the liver or spleen, which can be viewed as a disadvantage in that other organs and tissues are inaccessible. Thus, the application of this system to targeted delivery has been limited mainly to treatment of lysosomal storage diseases and metal toxicity, where the site of drug action is in the reticuloendothelial system.
Labeling of red blood cells with chromium-51 and white blood cells with indium-111, as well as labeling of liposomes with contrast media and therapeutic agents is known. U.S. Pat. No. 5,466,438 relates to liposoluble complexes of paramagnetic ions and compounds bearing long acyl chains useful as magnetic resonance imaging contrast agents. U.S. Pat. No. 5,000,960 relates to coupling a molecule having a free sulfhydryl group to a lipid vesicle having a free sulfhydryl group incorporated as one of the structural molecules of the lipid phase thereby forming a covalent disulfide bond linkage. U.S. Pat. No. 4,931,276 relates to methods for introducing desired agents into red blood cells, and U.S. Pat. No. 4,478,824 relates to methods and apparatus for causing reversible intracellular hypertonicity in red blood cells of mammals in order to introduce desired materials into the cells, or achieve therapeutically desirable changes in the characteristics of intracellular hemoglobin. Further, poor accumulation of liposomal cadmium-texaphyrin in tumor tissue was cited as a possible explanation for low efficiency of photodynaric therapy in König et al., (
Lasers in Surgery and Medicine
13:522, 1993; in: Photodynamic Therapy and Biomedical Lasers, P. Spinelli, M. Dal Fante and R. Marchesini, eds., Elsevier Science Publishers, 1992, 802).
Photodynamic therapy (PDT) is a treatment technique that uses a photosensitizing dye that produces cytotoxic materials, such as singlet oxygen (O
2
(
1
D
g
)) from benign precursors (e.g. ((O
2
(
3
S
g
—)), when irradiated in the presence of oxygen. Other reactive species such as superoxide, hydroperoxyl, or hydroxyl radicals may be involved. At the doses used, neither the light nor the drug has any independent activity against the disease target.
The effectiveness of PDT is predicated on three main factors: i) The photosensitive dyes used in PDT preferably have the ability to localize at the treatment site as opposed to surrounding tissue. ii) The high reactivity and short lifetime of activated oxygen means that it has a very short range and is unlikely to esc
Magda Darren
Mody Tarak D.
Sessler Jonathan L.
Wright Meredith
Young Stuart W.
Board of Regents , The University of Texas System
Jones Dameron L.
Kathardekar Vinit G.
LandOfFree
Membrane incorporation of texaphyrins does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Membrane incorporation of texaphyrins, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Membrane incorporation of texaphyrins will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2847868