Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Reexamination Certificate
1999-04-27
2001-08-14
Ceperley, Mary E. (Department: 1641)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
C424S009360, C424S009323, C424S009341, C424S601000, C436S526000, C436S806000, C530S391500
Reexamination Certificate
active
06274121
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to superparamagnetic particles consisting of superparamagnetic one-domain particles and aggregates of superparamagnetic one-domain particles of iron oxides, mixed iron oxides or iron to whose surfaces are bound inorganic substances which optionally may have further binding sites for coupling tissue-specific binding substances, diagnostic substances or pharmacologically active substances.
2. The Prior Art
Patent EP-B-0284549 describes superparamagnetic one-domain particles of iron oxide, mixed iron oxide or iron with a particle size ranging from 3 to 20 nanometres, to whose surfaces are chemically bound organic substances of the group of phosphate, diphosphate, polyphosphate, thiophosphate, phosphonate or thiophosphonate group-containing polyalkylene glycols, phosphate group-containing nucleotides, their oligomers or their polymers as well as phosphate group-containing carbohydrates, which may have further binding sites.
Patent DE-A-4309333 describes stable, degradable aggregates with a particle size ranging from between 10 and 1000 nanometres with defined behaviour in a magnetic field whereby the aggregates consist of several small superparamagnetic one-domain particles of iron oxide, mixed iron oxide or iron with a particle size ranging from 3 to 20 nanometres to whose surfaces are chemically bound substances of the group of phosphate, diphosphate, polyphosphate, thiophosphate, phosphonate or thiophosphonate group-containing polyalkylene glycols, carbohydrates or of the phosphate group-containing nucleotides, their oligomers or their polymers.
SUMMARY OF THE INVENTION
The object of the invention is to enlarge the range of substances which can be bound to the surfaces of the one-domain particles, in order to optimally adapt the physico-chemical and physiological properties of the magnetic particles being formed to the respective fields of application whereby these substances should be stable and easy to manufacture.
A surprising finding was that the inorganic ortho-silicic acid and their condensation products with bivalent and polyvalent inorganic ions and/or organic acids and bases and ortho- or metaphosphoric acid and their condensation products enter stable bindings with the surface of the superparamagnetic particles leading to stable magnetic liquids and aggregationstable, superparamagnetic aggregates.
According to the invention, stabilisation of the magnetic particles takes place by silicate group-containing substances of ortho-silicic acid and their condensation products with bivalent and polyvalent inorganic ions an/or organic acids and bases, of phosphate group containing substances of ortho- or metaphosphoric acid and their condensation products, on the surface of the magnetic particles.
Apart from these stabiliser substances, it is possible to bind additional organic substances to the surface of the magnetic particles in order to better adjust the properties of the magnetic particles to the desired requirements. This includes organic substances of the group of phosphate, diphosphate, carboxylate, polyphosphate, thiophosphate, phosphonate, thiophosphonate, sulphate, sulphonate, mercapto, carboxylate, silantriol group-containing polyalkylene glycols, and carbohydrates, of the phosphate group-containing nucleotides, their oligomers or their polymers, of the alkyl, aryl and/or alkylaryl-polyethylene glycol phosphates or phosphonates, of the group of nitrogenous polysaccharides, selected from among mucopolysaccharides, glycoproteids, chitins, as well as their derivatives and denaturation products.
By way of example, stabiliser substances for silicate group-containing condensation products of ortho-silicic acid with bi- and polyvalent inorganic ions are the condensation products with the elements Al, Au, Bi, Cr, J, Mo, P, Pt, Se, Tc, Ti, Y, Zr and rare precious metals.
By way of example, stabiliser substances for silicate group-containing condensation products of ortho-silicic acid with organic acids and bases are their condensation products with phytic acid, alginic acid, gallic acid.
By way of example, stabiliser substances of phosphate group-containing condensation products of ortho- or metaphosphoric acid are pyrophosphoric acid, polyphosphoric acids, cyclophospates and hetero condensation products and water insoluble salt compounds with inorganic ions, such as Ag, Au, Bi, Mo, Pt, Tc, Y, Zr, and basic group-containing organic compounds such as spermine, spermidine, polyethylene imine, oxygelatine.
The stabiliser substances may be manufactured according to the current state of technology, or purchased.
According to the invention, to the stabilisation molecules—to whose surfaces are bound silicate group-containing substances and phosphate group-containing substances at the surface of the super paramagnetic particles—the following can be bound: tissue-specific binding substances such as for example antigens, antibodies, ribonucleic acids, desoxyribonucleic acids, ribonucleic acid sequences, desoxyribonucleic acid sequences, haptens, avidin, streptavidin, protein A, protein G, endotoxin-binding proteins, lectin, selectin, pharmacologically active substances such as for example anti tumour proteins, enzymes, anti tumour enzymes, antibiotics, plant alkaloids, alkylation reagents, antimetabolites, hormones and hormone antagonists, interleukins, interferons, growth factors, tumour necrosis factors, endotoxins, lymphotoxins, urokinase, streptokinase, plasminogen-streptokinase activator complex, tissue plasminogen activators, desmodus plasminogen activators, macrophage activating bodies, antisera, protease inhibitors, substances containing radioactive isotopes, tensides, cardiovascular pharmaceutic products, chemotherapeutic products, gastrointestinal pharmaceutic products, neuropharmaceutic products, pharmacologically active cells such as for example organelles, viruses, microbes, algae, fungi, in particular erythrocytes, thrombocytes, granulocytes, monocytes, lymphocytes, Langerhans islands, pharmacologically active complexing agents, such as for example polycarbonic acids, polyaminocarboxylic acids, porphyrins, catecholamines, cell-fusioning substances such as for example polyethylene glycols, alkyl polyethylene glycols, alkyl aryl polyethylene glycols, water-miscible polypropylene glycols (PPG)
m
or water-miscible substance copolymerides of polyethylene glycol (PEG) and polypropylene glycol (PPG), selected from among the substance copolymerides (PEG)
n
—(PEG)
m
, (PEG)
n
—(PPG)
m
—(PEG)
n
, (PPG)
m
—(PEG)
n
—(PPG)
m
whereby n and m are positive whole numbers, selected for PEG in the range of 4 to 1000, for PPG in the range of 3 to 12 and for PEG-PPG substance copolymerides in the range 3 to 140, and/or substances acting as gene-transfer media, such as for example polyethylene glycols and their derivatives and polyalkylene imines, such as for example pentaethylene hexamine, polyethylene imine, spermine, spermidine.
The superparamagnetic particles according to the invention, which were stabilised with silicate group-containing substances of ortho-silicic acid and their condensation products with organic acids and bases, can be used for adsorptive bindings and for many coupling reactions during which the reactivity of the functional groups of the organic acids and basis which have formed stable condensation products with the silicate groups, for chemical binding of tissue-specific binding substances, pharmacologically active substances, pharmacologically active cells, pharmacologically active complexing agents, cell-fusioning substance and/or substance acting as gene-transfer medium is applicable.
The superparamagnetic particles according to the invention, which were stabilised with phosphate group-containing condensation and heterocondensation products and water insoluble salt compounds with inorganic ions, such as Ag, Au, Bi, Mo, Pt, Tc, Y, Zr, and basic group-containing organic compounds such as spermine, spermidine, polyethylene imine, oxygelatine, can be used for adsorptive bindings and
Ceperley Mary E.
Collard & Roe, P.C
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