US5055288A — Vascular magnetic imaging method and agent compri…

Claim 1

Independent Claim 171 words

A biodegradable superparamagnetic metal oxide comprising aggregates of individual biodegradable superparamagnetic hydrated metal oxide crystals, said metal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic metal oxide crystal; (iii) being capable of retaining anions in solution, characteristic of paramagnetic metal oxyhydroxides; (iv) 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, characteristic of sonicated superparamagnetic metal oxide crystal aggregates; and (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels.

Claim 2

Dependent Claim 171 words

A biodegradable superparamagnetic metal oxide comprising aggregates of individual biodegradable superparamagnetic hydrated metal oxide crystals, said metal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic metal oxide crystal; (iii) being capable of retaining anions in solution, characteristic of paramagnetic metal oxyhydroxides; (iv) 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, characteristic of sonicated superparamagnetic metal oxide crystal aggregates; and (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels.

Claim 3

Dependent Claim 176 words

A biodegradable superparamagnetic metal oxide comprising aggregates of individual biodegradable superparamagnetic hydrated metal oxide crystals associated with a macromolecular species, said metal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic metal oxide crystal; (iii) being capable of retaining anions in solution; characteristic of paramagnetic metal oxyhydroxides; (iv) 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, characteristic of sonicated superparamagnetic metal oxide crystal aggregates; about (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels.

Claim 4

Dependent Claim 176 words

A biodegradable superparamagnetic metal oxide comprising aggregates of individual biodegradable superparamagnetic hydrated metal oxide crystals associated with a macromolecular species, said metal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic metal oxide crystal; (iii) being capable of retaining anions in solution; characteristic of paramagnetic metal oxyhydroxides; (iv) 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, characteristic of sonicated superparamagnetic metal oxide crystal aggregates; about (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels.

Claim 5

Dependent Claim 29 words

The biodegradable superparamagnetic oxide of claim 1 or 2 in which said metal is selected from the group consisting of iron, cobalt, chromium, copper, manganese, molybdenum, nickel, and tungsten.

Claim 6

Dependent Claim 15 words

The biodegradable superparamagnetic oxide of claim 1 or 2 in which said metal is iron.

Claim 7

Dependent Claim 36 words

The biodegradable superparamagnetic oxide of claim 1 or 2 in which said metal oxide is selected from the group consisting of aggregates having an overall mean diameter less than about 3000, 2000, 1000, and 500 angstroms.

Claim 8

Dependent Claim 24 words

The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species has a molecular weight of about 1 to about 250 kilodaltons.

Claim 9

Dependent Claim 16 words

The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species is a carbohydrate.

Claim 10

Dependent Claim 15 words

The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species is dextran.

Claim 11

Dependent Claim 28 words

The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species and said metal are present in a weight ratio of about 0.01 to about 10.

Claim 12

Dependent Claim 28 words

The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species and said metal are present in a weight ratio of about 0.01 to about 0.2.

Claim 13

Dependent Claim 186 words

A sterilizable biodegradable superparamagnetic fluid which comprises: (a) a biodegradable superparamagnetic metal oxide comprising aggregates of individual biodegradable superparamagnetic hydrated metal oxide crystals, said metal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic metal oxide crystal; (iii) being capable of retaining anions in solution, characteristic of paramagnetic metal oxyhydroxides; (iv) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M 31 1 sec -1 , respectively, characteristic of sonicated superparamagnetic metal oxide crystal aggregates; and (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels; and (b) a physiologically acceptable medium.

Claim 14

Dependent Claim 186 words

A sterilizable biodegradable superparamagnetic fluid which comprises: (a) a biodegradable superparamagnetic metal oxide comprising aggregates of individual biodegradable superparamagnetic hydrated metal oxide crystals, said metal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic metal oxide crystal; (iii) being capable of retaining anions in solution, characteristic of paramagnetic metal oxyhydroxides; (iv) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M 31 1 sec -1 , respectively, characteristic of sonicated superparamagnetic metal oxide crystal aggregates; and (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels; and (b) a physiologically acceptable medium.

Claim 15

Dependent Claim 191 words

A sterilizable biodegradable superparamagnetic fluid which comprises: (a) a biodegradable superparamagnetic metal oxide comprising aggregates of individual biodegradable superparamagnetic hydrated metal oxide crystals associated with a macromolecular species, said metal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic metal oxide crystal; (iii) being capable of retaining anions in solutions, characteristic of paramagnetic metal oxyhydroxides: (iv) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M 31 1 sec 31 1, respectively, characteristic of sonicated superparamagnetic metal oxide crystal aggregates; and (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels; and (b) a physiologically acceptable medium.

Claim 16

Dependent Claim 191 words

A sterilizable biodegradable superparamagnetic fluid which comprises: (a) a biodegradable superparamagnetic metal oxide comprising aggregates of individual biodegradable superparamagnetic hydrated metal oxide crystals associated with a macromolecular species, said metal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic metal oxide crystal; (iii) being capable of retaining anions in solutions, characteristic of paramagnetic metal oxyhydroxides: (iv) being capable of producing proton relaxivity values, R 1 and R 2 , greater than or equal to about 10 4 and 10 5 M 31 1 sec 31 1, respectively, characteristic of sonicated superparamagnetic metal oxide crystal aggregates; and (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels; and (b) a physiologically acceptable medium.

Claim 17

Dependent Claim 36 words

The sterilizable biodegradable superparamagnetic fluid of claim 11 or 12 in which said medium comprises an aqueous solution of a polyfunctional organic molecule selected from the group consisting of polyphosphates, polyphosphinates, polyphosphonates, polysulfinates, polysulfonates, and polycarboxylates.

Claim 18

Dependent Claim 32 words

The sterilizable biodegradable superparamagnetic fluid of claim 11 or 12 in which said medium comprises an aqueous buffer selected from the group consisting of ethylenediamine polyacetate, citrate, tartrate, succinate, and maleatic buffers.

Claim 19

Dependent Claim 29 words

The sterilizable biodegradable fluid of claim 11 or 12 in which said medium comprises an aqueous buffer selected from the group consisting of sodium, potassium, and ammonium citrate buffers.

Claim 20

Dependent Claim 31 words

The sterilizable biodegradable fluid of claim 11 or 12 in which said medium contains added salt selected froam the group consisting of sodium chloride, potassium chloride, sodium iodide, and potassium iodide.

Claim 21

Dependent Claim 15 words

The sterilizable biodegradable fluid of claim 11 or 12 in which said metal is iron.

Claim 22

Dependent Claim 188 words

An autoclavable biodegradable superparamagnetic fluid which comprises: (a) a biodegradable superparamagnetic iron oxide comprising aggregates of individual biodegradable superparamagnetic hydrated iron oxide crystals associated with dextran, said meal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic iron oxide crystal; (iii) being capable of retaining anions in solutions, characteristic of paramagnetic iron oxyhydroxides; (iv) 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 31 1, respectively, characteristic of sonicated superparamagnetic iron oxide crystal aggregates; and (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels; and (b) an aqueous citrate buffer.

Claim 23

Dependent Claim 188 words

An autoclavable biodegradable superparamagnetic fluid which comprises: (a) a biodegradable superparamagnetic iron oxide comprising aggregates of individual biodegradable superparamagnetic hydrated iron oxide crystals associated with dextran, said meal oxide (i) having an individual crystal diameter of about 500 angstroms or less and aggregates with an overall mean diameter of about 4000 angstroms or less, as measured by light scattering methods; (ii) 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 a superparamagnetic iron oxide crystal; (iii) being capable of retaining anions in solutions, characteristic of paramagnetic iron oxyhydroxides; (iv) 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 31 1, respectively, characteristic of sonicated superparamagnetic iron oxide crystal aggregates; and (v) capable of being biodegraded in a subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue of such subject to preadministration levels; and (b) an aqueous citrate buffer.

Claim 24

Dependent Claim 17 words

The composition of claim 1, 2, 11, 12, or 18 which is further characterized as being hypotonic.

Claim 25

Dependent Claim 17 words

The composition of claim 1, 2, 11, 12, or 18 which is further characterized as being isotonic.

Claim 26

Dependent Claim 63 words

A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent (i) comprises a biodegradable superparamagnetic metal oxide, characterized as being metabolized or excreted by a subject within 30 days or less after administration, and (ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg per kg of rat.

Claim 27

Dependent Claim 63 words

A magnetic resonance imaging contrast agent in a physiologically acceptable medium, which contrast agent (i) comprises a biodegradable superparamagnetic metal oxide, characterized as being metabolized or excreted by a subject within 30 days or less after administration, and (ii) has a blood half-life in the rat of at least about 17 minutes at a dose of about 2 mg per kg of rat.

Claim 28

Dependent Claim 40 words

The contrast agent of claim 21 in which said metal oxide is biodegraded in such subject within about two weeks or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue to pre-administration levels.

Claim 29

Dependent Claim 40 words

The contrast agent of claim 21 in which said metal oxide is biodegraded in such subject within about one week or less after administration, as evidenced by a return of the proton relaxation rates of affected tissue to pre-administration levels.

Claim 30

Dependent Claim 20 words

The contrast agent of claim 21, 22 or 23 in which said metal oxide is associated with a macromolecular species.

Claim 31

Dependent Claim 17 words

The contrast agent of claim 24 in which said macromolecular species is a polysaccharide or mixtures thereof.

Claim 32

Dependent Claim 15 words

The contrast agent of claim 21, 22 or 23 in which said metal is iron.

Claim 33

Dependent Claim 19 words

The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species is a polysaccharide or mixtures thereof.

Claim 34

Dependent Claim 44 words

The biodegradable superparamagnetic metal oxide of claim 1, 2, 11 or 12 in which the individual crystal diameter is about 100 angstroms or less and the overall mean diameter of the aggregates is about 500 angstroms or less, as measured by light scattering methods.

Claim 35

Dependent Claim 26 words

The contrast agent of claim 24 which is further characterized as being capable of exerting a brightening effect upon administration to an animal or human subject.

Claim 36

Dependent Claim 26 words

The contrast agent of claim 24 which is further characterized as being capable of exerting a darkening effect upon administration to an animal or human subject.

Claim 37

Dependent Claim 38 words

The contrast agent of claim 24 which is further characterized as being capable of exerting a contrast effect that is a combination of a brightening effect and a darkening effect upon administration to an animal or human subject.

Claim 38

Dependent Claim 33 words

The contrast agent of claim 21, 22 or 23 in which said blood half-life in the rate is at least about 50 minutes at a dose of 2 mg per kg of rat.

Claim 39

Dependent Claim 14 words

The contrast agent of claim 21, 22, 24 in which said metal is iron.

Claim 40

Dependent Claim 35 words

The contrast agent of claim 24 in which said metal oxide is comprised of one or more biodegradable superparamagnetic metal oxide crystals, said crystals having an overall mean diameter of about 100 angstroms or less.

Claim 41

Dependent Claim 32 words

The contrast agent of claim 24 in which said metal oxide is comprised of aggregates of metal oxide crystals, said aggregates having an overall mean diameter of about 3000 angstroms or less.

Claim 42

Dependent Claim 32 words

The contrast agent of claim 24 in which said metal oxide is comprised of aggregates of metal oxide crystals, said aggregates having an overall mean diameter of about 2000 angstroms or less.

Claim 43

Dependent Claim 32 words

The contrast agent of claim 24 in which said metal oxide is comprised of aggregates of metal oxide crystals, said aggregates having an overall mean diameter of about 1000 angstroms or less.

Claim 44

Dependent Claim 32 words

The contrast agent of claim 24 in which said metal oxide is comprised of aggregates of metal oxide crystals, said aggregates having an overall mean diameter of about 500 angstroms or less.

Claim 45

Dependent Claim 54 words

The contrast agent of claim 21, 22 or 23 in which said meal oxide is comprised of one or more biodegradable superparamagnetic meal oxide crystals, each crystal having a diameter of about 100 angstroms or less and the largest aggregate of metal oxide crystals having an overall mean diameter not exceeding about 500 angstroms.

Claim 46

Dependent Claim 51 words

The contrast agent of claim 24 in which said metal oxide is comprised of one or more biodegradable superparamagnetic metal oxide crystals, each crystal having a diameter of about 100 angstroms or less and the largest aggregates of metal oxide crystals having an overall mean diameter not exceeding about 500 angstroms.

Claim 47

Dependent Claim 12 words

The contrast agent of claim 25 in which said metal is iron.

Claim 48

Dependent Claim 30 words

The contrast agent of claim 24 in which said blood half-life in the rat is at least about 50 minutes at a dose of 2 mg per kg of rat.

Claim 49

Dependent Claim 30 words

The contrast agent of claim 25 in which said blood half-life in the rat is at least about 50 minutes at a dose of 2 mg per kg of rat.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1994-10-07	1995-04-08	1995-10-08	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1998-10-07	1999-04-08	1999-10-08	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2002-10-07	2003-04-08	2003-10-08	$7700.00	Window Closed / Lapsed

Vascular magnetic imaging method and agent comprising biodegradeable superparamagnetic metal oxides

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