US4827945A
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US
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Biologically degradable superparamagnetic materials for use in clinical applications
Assignee: Amag Pharmaceuticals Inc
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Filing: 1987-06-26
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Granted: 1989-05-09
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Expires: 2007-06-26
Abstract
Abstract This invention relates to materials exhibiting certain magnetic and biological properties which make them uniquely suitable for use as magnetic resonance imaging (MRI) agents to enhance MR images of animal organs and tissues. More particularly, the invention relates to the in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. These materials are administered to animals, including humans, by a variety of routes and the metal oxides therein collect in specific target organs to be imaged; in the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image. In addition, the dispersoids and fluids are quite stable and, in the case of the fluids, can even be subjected to autoclaving without impairing their utility. Furthermore, the materials are biodegradable and, in the case of iron oxide compounds, can eventually be incorporated into the subject's hemoglobin, making them useful in treating anemia. Thus, the materials are well-suited for in vivo use.
Inventors
- 👤 Ernest V. Groman
- 👤 Lee Josephson
- 👤 Jerome M. Lewis
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 13:34
CPC Classifications
B; B82; B82Y; B82Y5/00; A; A61; A61K; A61K49/00; A61K49/06; A61K49/18; A61K49/1806; A61K49/1818; A61K49/1821; A61K49/1824; A61K49/1827; A61K49/1851; A61K49/1863; A61K49/1866; A61K49/1869; A61P; A61P7/00; A61P7/06; C; C08; C08G; C08G18/00; C08G18/06; C08G18/08; C08G18/16; C08G18/18; C08G18/1808; C08G18/1816; C08G18/1825; C08G18/20; C08G18/2009; C08G18/2036; C08G18/22; C08G18/24; C08G18/244; C08G18/246; C08G18/26; C08J; C08J9/00; C08J9/04; C08J9/12; C08J9/14; C08J9/143; C08J9/144; G; G01; G01R; G01R33/00; G01R33/20; G01R33/44; G01R33/48; G01R33/54; G01R33/56; G01R33/5601; C08G2101/00; C08J2375/00; C08J2375/04
Claims Analysis
Total Claims: 47
Claim 1
Independent Claim
210 words
A method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject which comprises administering to such a subject as a contrast agent an effective amount of a hiodegradable superparamagnetic metal oxide in a physiologically acceptable carrier, said metal oxide (i) having a magnetic saturation between about 5 and about 90 EMU/g of metal oxide at approximately 300° K. and a magnetic squareness of less than 0.1, characteristic of superparamagnetic metal oxide crystals; (ii) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M -1 sec -1 , respectively; (iii) being capable of retaining anions in solution in a manner chacteristic of paramagnetic metal oxyhydroxides; comprising one or more biodegradable metal oxide crystals, each crystal about 10 to about 500 angstroms in diameter, and having an overall diameter of about 10 to about 4000 angstroms as measured by light scattering; (v) being capable of forming aqueous solutions up to a concentration of about 5 molar; and further characterized as having a retention time in said organ or tissue sufficiently long to permit an image to be obtained and being ultimately biodegraded; and (b) obtaining such MR image.
Claim 2
Independent Claim
210 words
A method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject which comprises administering to such a subject as a contrast agent an effective amount of a hiodegradable superparamagnetic metal oxide in a physiologically acceptable carrier, said metal oxide (i) having a magnetic saturation between about 5 and about 90 EMU/g of metal oxide at approximately 300° K. and a magnetic squareness of less than 0.1, characteristic of superparamagnetic metal oxide crystals; (ii) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M -1 sec -1 , respectively; (iii) being capable of retaining anions in solution in a manner chacteristic of paramagnetic metal oxyhydroxides; comprising one or more biodegradable metal oxide crystals, each crystal about 10 to about 500 angstroms in diameter, and having an overall diameter of about 10 to about 4000 angstroms as measured by light scattering; (v) being capable of forming aqueous solutions up to a concentration of about 5 molar; and further characterized as having a retention time in said organ or tissue sufficiently long to permit an image to be obtained and being ultimately biodegraded; and (b) obtaining such MR image.
Claim 3
Independent Claim
217 words
A method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject which comprises (a) administering to such a subject as a contrast agent an effective amount of a biodegradable superparamagnetic metal oxide associated with a polymeric substance in a physiologically acceptable carrier, said metal oxide (i) having a magnetic saturation between about 5 and about 90 EMU/g of metal oxide at approximately 300° K. and a magnetic squareness of less than 0.1, characteristic of superparamagnetic metal oxide crystals; (ii) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M -1 sec -1 , respectively; (iii) being capable of retaining anions in solution in a manner characteristic of paramagnetic metal oxyhydroxides; comprising one or more biodegradable metal oxide crystals, each crystal about 10 to about 500 angstroms in diameter, and having an overall mean diameter of about 10 to about 4000 angstroms as measured by light scattering; (v) being capable of forming aqueous solutions up to a concentration of about 5 molar; and further characterized as having a retention time in said organ or tissue sufficiently long to permit an image to be obtained and being ultimately biograded; and (b) obtaining such MR image.
Claim 4
Independent Claim
217 words
A method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject which comprises (a) administering to such a subject as a contrast agent an effective amount of a biodegradable superparamagnetic metal oxide associated with a polymeric substance in a physiologically acceptable carrier, said metal oxide (i) having a magnetic saturation between about 5 and about 90 EMU/g of metal oxide at approximately 300° K. and a magnetic squareness of less than 0.1, characteristic of superparamagnetic metal oxide crystals; (ii) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M -1 sec -1 , respectively; (iii) being capable of retaining anions in solution in a manner characteristic of paramagnetic metal oxyhydroxides; comprising one or more biodegradable metal oxide crystals, each crystal about 10 to about 500 angstroms in diameter, and having an overall mean diameter of about 10 to about 4000 angstroms as measured by light scattering; (v) being capable of forming aqueous solutions up to a concentration of about 5 molar; and further characterized as having a retention time in said organ or tissue sufficiently long to permit an image to be obtained and being ultimately biograded; and (b) obtaining such MR image.
Claim 5
Independent Claim
278 words
A method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject which comprises, (a) administering to such a subject an effective amount of a superparamagnetic fluid comprising a biodegradable superparamagnetic contrast agent, selected from the group consisting of a metal oxide and a metal oxide associated with a polymeric substance, in an aqueous polycarboxylic acid buffer, said metal oxide: (i) having a magnetic saturation between about 5 and about 90 EMU/g of metal oxide at approximately 300° K. and a magnetic squareness of less than 0.1, characteristic of superparamagnetic metal oxide crystals; (ii) being capable of producing proton relaxivity values, R 1 an R 2 , greater than or equal to about 10 4 and 10 5 M -1 sec -1 , respectively; (iii) being capable of retaining anions in solution in a manner characteristic of paramagnetic metal oxyhydroxides; (iv) comprising one or more biodegradable metal oxide crystals, each crystal about 10 to about 500 angstroms in diameter, and having an overall mean diameter of about 10 to about 4000 angstroms as measured by light scattering; (v) being capable of forming aqueous solutions up to a concentration of about 5 molar; (vi) characterized as having a retention time in said organ or tissue sufficiently long to permit an image to be obtained and being ultimately biodegraded; and in which said buffer is further characterized by: (vii) a metal concentration ranging from 0.05 to 5 molar; (viii) a polycarboxylate counterion concentration ranging from 0.001 to about 0.1 moles of polycarboxylate per mole of metal; and (ix) a pH between about 6 and about 8.3 and (b) obtaining such MR image.
Claim 6
Independent Claim
278 words
A method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject which comprises, (a) administering to such a subject an effective amount of a superparamagnetic fluid comprising a biodegradable superparamagnetic contrast agent, selected from the group consisting of a metal oxide and a metal oxide associated with a polymeric substance, in an aqueous polycarboxylic acid buffer, said metal oxide: (i) having a magnetic saturation between about 5 and about 90 EMU/g of metal oxide at approximately 300° K. and a magnetic squareness of less than 0.1, characteristic of superparamagnetic metal oxide crystals; (ii) being capable of producing proton relaxivity values, R 1 an R 2 , greater than or equal to about 10 4 and 10 5 M -1 sec -1 , respectively; (iii) being capable of retaining anions in solution in a manner characteristic of paramagnetic metal oxyhydroxides; (iv) comprising one or more biodegradable metal oxide crystals, each crystal about 10 to about 500 angstroms in diameter, and having an overall mean diameter of about 10 to about 4000 angstroms as measured by light scattering; (v) being capable of forming aqueous solutions up to a concentration of about 5 molar; (vi) characterized as having a retention time in said organ or tissue sufficiently long to permit an image to be obtained and being ultimately biodegraded; and in which said buffer is further characterized by: (vii) a metal concentration ranging from 0.05 to 5 molar; (viii) a polycarboxylate counterion concentration ranging from 0.001 to about 0.1 moles of polycarboxylate per mole of metal; and (ix) a pH between about 6 and about 8.3 and (b) obtaining such MR image.
Claim 7
Dependent Claim
37 words
The method of claim 3 in which said metal is iron, and the aqueous polycarboxylic acid buffer is selected from the group consisting of aqueous citrate buffer, aqueous tartrate buffer, aqueous succinate buffer, and aqueous maleatic buffers.
Claim 8
Dependent Claim
27 words
The method of claim 3 wherein the metal concentration is about 1.3 molar iron, the citrate concentration is about 0.04 molar, and the ph is about 7.
Claim 9
Dependent Claim
24 words
The method of claim 2 wherein the polymeric substance is selected from the group consisting of polysacharides, carbohydrates, polypeptides, organosilanes, proteins, and composites thereof.
Claim 10
Dependent Claim
21 words
The method of claim 2 wherein the polymeric substance consists of dextran having a molecular weight between 5,000 and 250,000 daltons.
Claim 11
Dependent Claim
11 words
The method of claim 2 wherein the polymeric substance is albumin.
Claim 12
Dependent Claim
14 words
The method of claim 2 wherein the polymeric substance is a polymer of N-2-aminoethyl-3-aminopropyltrimethoxysilane.
Claim 13
Dependent Claim
17 words
The method of claim 3 wherein said superparamagnetic fluid is administered to the subject by intravascular injection.
Claim 14
Dependent Claim
29 words
The method of claim 3 wherein said superparamagnetic fluid is administered to the subject by a method selected from the group consisting of oral administration, intubation, and by enema.
Claim 15
Dependent Claim
17 words
The method of claim 3 wherein the organ or tissue imaged is part of the reticuloendothelial system.
Claim 16
Dependent Claim
24 words
The method of claim 3 wherein the organ or tissue imaged is selected from the group consisting of a liver, spleen, and bone marrow.
Claim 17
Dependent Claim
17 words
The method of claim 3 wherein the organ or tissue imaged is part of the lymphatic system.
Claim 18
Dependent Claim
15 words
The method of claim 3 wherein the organ or tissue imaged is a lymph node.
Claim 19
Dependent Claim
17 words
The method of claim 3 wherein the organ or tissue imaged is part of the nervous system.
Claim 20
Dependent Claim
26 words
The method of claim 3 wherein the organ or tissue imaged is selected from the group consisting of the brain, the spinal cord, and parts thereof.
Claim 21
Dependent Claim
17 words
The method of claim 3 wherein the organ or tissue imaged is part of the vascular compartment.
Claim 22
Dependent Claim
23 words
The method of claim 3 wherein the organ or tissue imaged is selected from the group consisting of blood capillaries and lymph vessels.
Claim 23
Dependent Claim
14 words
The method of claim 3 wherein the organ or tissue imaged is a lung.
Claim 24
Dependent Claim
18 words
The method of claim 3 wherein the organ or tissue imaged is a part of the gastrointestinal tract.
Claim 25
Dependent Claim
26 words
The method of claim 3 wherein the organ or tissue imaged is selected from the group consisting of an esophagus, stomach, small intestine, and large intestine.
Claim 26
Dependent Claim
65 words
The method of claim 2 in which said metal oxide further comprises an effective amount of a biological molecule covalently coupled to said polymeric substance, said biological molecule possessing at least one functional group which is recognized by receptors in various organs and tissues of the subject, such that said metal oxide is directed invivo to the organ or tissue which recognizes said biological molecule.
Claim 27
Dependent Claim
12 words
The method of claim 23 wherein the biological molecule is an antibody.
Claim 28
Dependent Claim
20 words
The method of claim 24 wherein the antibody is an anti-melanoma antibody and the tissue being imaged is melanoma tissue.
Claim 29
Dependent Claim
22 words
The method of claim 24 wherein the antibody is an anti-heart myosin antibody and the tissue being imaged is infarcted heart tissue.
Claim 30
Dependent Claim
20 words
The method of claim 24 wherein the antibody is an anti-T-cell antibody and the tissue being imaged is lymphoma tissue.
Claim 31
Dependent Claim
21 words
The method of claim 24 wherein the antibody is anti-carcinomic embryonic antigens and the tissue being imaged is colonic tumor tissue.
Claim 32
Dependent Claim
23 words
The method of claim 24 wherein the antibody is an anti-ovarian cancer cell antibody and the tissue being imaged is ovarian cancer tissue.
Claim 33
Dependent Claim
12 words
The method of claim 23 wherein the biological molecule is a carbohydrate.
Claim 34
Dependent Claim
12 words
The method of claim 23 wherein the biological molecule is a hormone.
Claim 35
Independent Claim
77 words
The method for extending the serum lifetime of a superparamagnetic MR contrast agent in an animal or human subject comprising the steps of: (i) administering to said subject an effective amount of blocking agent in a physiologically acceptable carrier, said blocking agent being capable of competitively binding to reticuloendothelial system (RES) receptors which can remove said contrast agent from circulation; and (ii) subsequently or simultaneously administering to the same subject an effective amount of said contrast agent.
Claim 36
Independent Claim
77 words
The method for extending the serum lifetime of a superparamagnetic MR contrast agent in an animal or human subject comprising the steps of: (i) administering to said subject an effective amount of blocking agent in a physiologically acceptable carrier, said blocking agent being capable of competitively binding to reticuloendothelial system (RES) receptors which can remove said contrast agent from circulation; and (ii) subsequently or simultaneously administering to the same subject an effective amount of said contrast agent.
Claim 37
Dependent Claim
11 words
The method of claim 32 wherein the blocking agent is paramagnetic.
Claim 38
Dependent Claim
24 words
The method of claim 32 wherein the contrast agent is a biodegradable superparamagnetic iron oxide and the blocking agent is a paramagnetic iron oxide.
Claim 39
Independent Claim
111 words
A method for detecting in vivo blood flow in an animal or human subject comprising the steps of: (i) administering to said subject an effective amount of a dispersoid of a blocking agent in a physiologically acceptable carrier, said blocking agent being recognized by RES receptors; (ii) subsequently administering to said subject a dispersoid or solution of a superparamagnetic MR contrast agent in a physiologically acceptable carrier, said MR contrast agent competing for the sam RES receptors as said blocking agent is step (i); (iii) obtaining an MR image of the blood in a section of the subject; and (iv) detecting the presence or absence of blood flow in the section.
Claim 40
Independent Claim
111 words
A method for detecting in vivo blood flow in an animal or human subject comprising the steps of: (i) administering to said subject an effective amount of a dispersoid of a blocking agent in a physiologically acceptable carrier, said blocking agent being recognized by RES receptors; (ii) subsequently administering to said subject a dispersoid or solution of a superparamagnetic MR contrast agent in a physiologically acceptable carrier, said MR contrast agent competing for the sam RES receptors as said blocking agent is step (i); (iii) obtaining an MR image of the blood in a section of the subject; and (iv) detecting the presence or absence of blood flow in the section.
Claim 41
Dependent Claim
11 words
The method of claim 35 wherein the blocking agent is paramagnetic.
Claim 42
Dependent Claim
26 words
The method of claim 35 wherein the superparamagnetic MR contrast agent is a biodegradable superparamagnetic iron oxide and the blocking agent is a paramagnetic iron oxide.
Claim 43
Independent Claim
135 words
A method for reducing anemia in an animal or human subject comprising parenterally administering to such a subject an effective amount of a dispersoid comprising a biodegradable superparamagnetic agent, selected from the group consisting of iron oxide particles and iron oxide particles associated with a polymeric substance, dispersed in a physiologically acceptable carrier, an individual particle (i) comprising one or more biodegradable iron oxide crystals, each crystal about 10 to about 500 angstroms in diameter; (ii) having an overall mean diameter, inclusive of any olymeric substance, of about 10 to about 5000 angstroms as measured by light scattering; (iii) having a surface area greater than about 75 m 2 /g; (iv) having a magnetic saturation between about 5 and about 90 EMU/g of iron oxide; and (v) possessing a magnetic squareness of less than 0.1.
Claim 44
Independent Claim
135 words
A method for reducing anemia in an animal or human subject comprising parenterally administering to such a subject an effective amount of a dispersoid comprising a biodegradable superparamagnetic agent, selected from the group consisting of iron oxide particles and iron oxide particles associated with a polymeric substance, dispersed in a physiologically acceptable carrier, an individual particle (i) comprising one or more biodegradable iron oxide crystals, each crystal about 10 to about 500 angstroms in diameter; (ii) having an overall mean diameter, inclusive of any olymeric substance, of about 10 to about 5000 angstroms as measured by light scattering; (iii) having a surface area greater than about 75 m 2 /g; (iv) having a magnetic saturation between about 5 and about 90 EMU/g of iron oxide; and (v) possessing a magnetic squareness of less than 0.1.
Claim 45
Independent Claim
239 words
A method for reducing anemia in an animal or human subject comprising parenterally administering to such a subject an effective amount of a superparamagnetic fluid comprising a biodegradable superparamagnetic agent, selected from the group consisting of an iron oxide and an iron oxide associated with a polymeric substance, in an aqueous polycarboxylic acid buffer, said iron oxide: (i) having a magnetic saturation between about 5 and about 90 EMU/g of iron oxide at approximately 300° K. and a magnetic squareness of less than 0.1, characteristic of superparamagnetic iron oxide crystals; (ii) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M -1 sec -1 , respectively; (iii) being capable of retaining anions in solution in a manner characteristic of paramagnetic iron oxyhydroxides; (iv) further comprising one or more biodegradable iron oxide crystals, each crystal about 10 to about 500 angstroms in diameter, and having an overall mean diameter of about 10 to about 4000 angstroms as measured by light scattering; (v) being capable of forming aqueous solutions up to a concentration of about 5 molar; and in which said buffer is further characterized by: (vi) an iron concentration ranging from about 0.05 to about 5 molar; (vii) a polycarboxylate counterion concentration ranging from 0.001 to about 0.1 moles of polycarboxylate per mole of iron; an (viii) a pH between about 6 and about 8.3.
Claim 46
Independent Claim
239 words
A method for reducing anemia in an animal or human subject comprising parenterally administering to such a subject an effective amount of a superparamagnetic fluid comprising a biodegradable superparamagnetic agent, selected from the group consisting of an iron oxide and an iron oxide associated with a polymeric substance, in an aqueous polycarboxylic acid buffer, said iron oxide: (i) having a magnetic saturation between about 5 and about 90 EMU/g of iron oxide at approximately 300° K. and a magnetic squareness of less than 0.1, characteristic of superparamagnetic iron oxide crystals; (ii) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M -1 sec -1 , respectively; (iii) being capable of retaining anions in solution in a manner characteristic of paramagnetic iron oxyhydroxides; (iv) further comprising one or more biodegradable iron oxide crystals, each crystal about 10 to about 500 angstroms in diameter, and having an overall mean diameter of about 10 to about 4000 angstroms as measured by light scattering; (v) being capable of forming aqueous solutions up to a concentration of about 5 molar; and in which said buffer is further characterized by: (vi) an iron concentration ranging from about 0.05 to about 5 molar; (vii) a polycarboxylate counterion concentration ranging from 0.001 to about 0.1 moles of polycarboxylate per mole of iron; an (viii) a pH between about 6 and about 8.3.
Claim 47
Dependent Claim
15 words
The method of claim 3 wherein said superparamagnetic fluid is administered to the subject parenterally.
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