US5314679A
Expired / Lapsed
US
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Vascular magnetic resonance imaging agent comprising nanoparticles
Assignee: Amag Pharmaceuticals Inc
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Filing: 1992-12-22
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Granted: 1994-05-24
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Expires: 2012-12-22
Abstract
Abstract The preparation and isolation of biodegradable superparamagnetic MR imaging contrast agents for the vascular compartment is described. These aggregates are comprised of individual biodegradable superparamagnetic metal oxide crystals which aggregates have an overall mean diameter less than about 4000 angstroms. The preferred vascular imaging contrast agent is comprised of aggregates of iron oxide crystals having an overall mean diameter less than about 500 angstroms. These contrast agents may be associated with a macromolecular species, which assist, among other things, in the preparation of these extremely small materials, and may be dispersed or dissolved in a physiologically acceptable medium. Preferred media also stabilize the materials against further aggregation even under harsh sterilization conditions. The autoclaved biodegradable superparamagnetic iron oxides of the invention are ideally suited for a pharmaceutical preparation and enjoy several advantages over prior intravascular imaging contrast media including low osmolality, low effective dose requirements, high relaxivities, long blood lifetimes, rapid biodegradability, and versatility with respect to a wide range of applicable MR data acquisition parameters.
Inventors
- 👤 Jerome M. Lewis
- 👤 Edward T. Menz
- 👤 Francis E. Kenny
- 👤 Ernest V. Groman
- 👤 Lee Josephson
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 15:28
CPC Classifications
G; G01; G01R; G01R33/00; G01R33/20; G01R33/44; G01R33/48; G01R33/54; G01R33/56; G01R33/5601; A; A61; A61K; A61K49/00; A61K49/06; A61K49/18; A61K49/1818; A61K49/1821; A61K49/1824; A61K49/1827; A61K49/1851; A61K49/1863; B; B82; B82Y; B82Y5/00; 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; C08G2101/00; C08J2375/00; C08J2375/04; Y; Y10; Y10S; Y10S436/00; Y10S436/806; Y10T; Y10T436/00; Y10T436/24
Claims Analysis
Total Claims: 48
Claim 1
Independent Claim
100 words
A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent: i) comprises a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return by proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels; and (b) are associated with a protein; and ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.
Claim 2
Dependent Claim
100 words
A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent: i) comprises a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return by proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels; and (b) are associated with a protein; and ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.
Claim 3
Dependent Claim
99 words
A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent: (i) comprises a population of biodegradable superparamagnetic metal oxide, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a polypeptide; and (ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.
Claim 4
Dependent Claim
99 words
A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent: (i) comprises a population of biodegradable superparamagnetic metal oxide, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a polypeptide; and (ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.
Claim 5
Dependent Claim
99 words
A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent: (i) comprises a population of biodegradable metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with hydroxethyl starch; and (ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.
Claim 6
Dependent Claim
99 words
A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent: (i) comprises a population of biodegradable metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with hydroxethyl starch; and (ii) has a blood half-life in the rate of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat.
Claim 7
Dependent Claim
29 words
The magnetic resonance imaging contrast agent of claim 1 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.
Claim 8
Dependent Claim
23 words
The magnetic resonance imaging contrast agent of claim 2 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.
Claim 9
Dependent Claim
25 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.
Claim 10
Dependent Claim
33 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said metal oxide is selected from the group consisting of chromium, cobalt, copper, manganese, molybdenum, nickel and tungsten oxides.
Claim 11
Dependent Claim
20 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said metal oxide is iron oxide.
Claim 12
Dependent Claim
37 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 which comprises a population of particles wherein the mean diameter of an individual particle is about 180 Å or less, as measured by light scattering.
Claim 13
Dependent Claim
36 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said blood half-life is at least about 49 minutes in rat at a dose of 2 mg per metal per kg rat.
Claim 14
Dependent Claim
29 words
The magnetic resonance imaging contrast agent of claim 10 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.
Claim 15
Dependent Claim
23 words
The magnetic resonance imaging contrast agent of claim 10 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.
Claim 16
Dependent Claim
22 words
The magnetic resonance imaging contrast agent of claim 10 in which said particles comprises aggregates of individual biodegradable superparamagnetic metal oxide crystals.
Claim 17
Dependent Claim
34 words
The magnetic resonance imaging contrast agent of claim 10 which comprises a population of particles wherein the mean diameter of an individual particle is about 150 Å or less, as measured by light scattering.
Claim 18
Dependent Claim
23 words
The magnetic resonance imaging contrast agent of claim 14 in which said polypeptides is selected from the group consisting of polyglutamate and polylysine.
Claim 19
Dependent Claim
22 words
The magnetic resonance imaging contrast agent of claim 14 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.
Claim 20
Dependent Claim
30 words
The magnetic resonance contrast imaging contrast agent of claim 14 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin, and heparin.
Claim 21
Dependent Claim
28 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said macromolecular species has a molecular weight of about 1 to about 250 kd.
Claim 22
Dependent Claim
32 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said macromolecular species and said metal are present at a weight ratio of about 0.1 to about 10.
Claim 23
Dependent Claim
31 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said macromolecular species and said metal are present at a weight ratio of about 0.01 to 0.2.
Claim 24
Dependent Claim
43 words
The magnetic resonance imaging contrast agent of claim 1, 2 or 3 in which said contrast agent is capable of providing a contrast effect selected from the group consisting of a darkening effect, a brightening effect, and a combined darkening and brightening effect.
Claim 25
Independent Claim
140 words
A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises: (a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent; (i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a protein; and (ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat; and (b) recording such MR image of the vascular compartment.
Claim 26
Independent Claim
140 words
A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises: (a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent; (i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a protein; and (ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg of metal per kg of rat; and (b) recording such MR image of the vascular compartment.
Claim 27
Independent Claim
139 words
A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises: (a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent (i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a polypeptide; and (ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg metal per kg of rat; and (b) recording such MR image of the vascular compartment.
Claim 28
Independent Claim
139 words
A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises: (a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent (i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a polypeptide; and (ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg metal per kg of rat; and (b) recording such MR image of the vascular compartment.
Claim 29
Independent Claim
140 words
A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises: (a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent (i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a hydroxyethyl starch; and (ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg metal per kg of rat; and (b) recording such MR image of the vascular compartment.
Claim 30
Independent Claim
140 words
A method for obtaining an MR image of the vascular compartment of an animal or a human subject which comprises: (a) administering to such a subject, an effective amount of a magnetic resonance imaging contrast agent in a physiologically acceptable medium, said contrast agent (i) comprising a population of biodegradable superparamagnetic metal oxide particles, wherein said particles (a) are capable of being metabolized or excreted by a subject within about 1 week after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of the subject to pre-administration levels, and (b) are associated with a hydroxyethyl starch; and (ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg metal per kg of rat; and (b) recording such MR image of the vascular compartment.
Claim 31
Dependent Claim
25 words
The method of claim 22 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.
Claim 32
Dependent Claim
19 words
The method of claim 21 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.
Claim 33
Dependent Claim
21 words
The method of claim 22, 23 or 24 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.
Claim 34
Dependent Claim
29 words
The method of claim 22, 23 or 24 in which said metal oxide is selected from the group consisting of chromium, cobalt, copper, manganese, molybdenum, nickel and tungsten oxides.
Claim 35
Dependent Claim
16 words
The method of claim 22, 23 or 24 in which said metal oxide is iron oxide.
Claim 36
Dependent Claim
33 words
The method of claim 22, 23 or 24 which comprises a population of particles wherein the mean diameter of an individual particle is about 180 Å or less, as measured by light scattering.
Claim 37
Dependent Claim
32 words
The method of claim 22, 23 or 24 in which said blood half-life is at least about 49 minutes in rat at a dose of 2 mg per metal per kg rat.
Claim 38
Dependent Claim
34 words
The method of claim 22, 23 or 24 in which comprises a population of particles wherein the mean diameter of an individual particle is about 150 Å or less, as measured by light scattering.
Claim 39
Dependent Claim
23 words
The method of claim 22, 23 or 24 in which said macromolecular species has a molecular weight of about 1 to 250 kd.
Claim 40
Dependent Claim
28 words
The method of claim 22, 23 or 24 in which said macromolecular species and said metal are present at a weight ratio of about 0.01 to about 10.
Claim 41
Dependent Claim
28 words
The method of claim 22, 23 or 24 in which said macromolecular species and said metal are present at a weight ratio of about 0.01 to about 0.2.
Claim 42
Dependent Claim
39 words
The method of claim 22, 23 or 24 in which said contrast agent is capable of providing a contrast effect selected from the group consisting of a darkening effect, a brightening effect, and a combined darkening and brightening effect.
Claim 43
Dependent Claim
25 words
The method of claim 31 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.
Claim 44
Dependent Claim
19 words
The method of claim 31 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.
Claim 45
Dependent Claim
18 words
The method of claim 31 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.
Claim 46
Dependent Claim
25 words
The method of claim 32 in which said protein is selected from the group consisting of human serum albumin, bovine serum albumin, gelatin and heparin.
Claim 47
Dependent Claim
19 words
The method of claim 32 in which said polypeptide is selected from the group consisting of polyglutamate and polylysine.
Claim 48
Dependent Claim
18 words
The method of claim 32 in which said particles comprise aggregates of individual biodegradable superparamagnetic metal oxide crystals.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1997-05-23 | 1997-11-22 | 1998-05-24 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2001-05-23 | 2001-11-22 | 2002-05-24 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2005-05-23 | 2005-11-22 | 2006-05-24 | $7700.00 | Window Closed / Lapsed |