Claims for Patent: 5,055,288

Summary for Patent: 5,055,288

Title:	Vascular magnetic imaging method and agent comprising biodegradeable superparamagnetic metal oxides
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.
Inventor(s):	Lewis; Jerome M. (Newton, MA), Menz; Edward T. (Quincy, MA), Kenny; Francis E. (Watertown, MA), Groman; Ernest V. (Brookline, MA), Josephson; Lee (Arlington, MA)
Assignee:	Advanced Magnetics, Inc. (Cambridge, MA)
Application Number:	07/233,177
Patent Claims:	1. 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.degree. 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.sub.1 and R.sub.2, greater than or equal to about 10.sup.4 and 10.sup.5 M.sup.-1 sec.sup.-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. 2. 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.degree. 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.sub.1 and R.sub.2, greater than or equal to about 10.sup.4 and 10.sup.5 M.sup.-1 sec.sup.-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. 3. 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. 4. The biodegradable superparamagnetic oxide of claim 1 or 2 in which said metal is iron. 5. 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. 6. The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species has a molecular weight of about 1 to about 250 kilodaltons. 7. The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species is a carbohydrate. 8. The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species is dextran. 9. 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. 10. 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. 11. 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.degree. 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.sub.1 and R.sub.2, greater than or equal to about 10.sup.4 and 10.sup.5 M.sup.31 1 sec.sup.-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. 12. 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.degree. 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.sub.1 and R.sub.2, greater than or equal to about 10.sup.4 and 10.sup.5 M.sup.31 1 sec.sup.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. 13. 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. 14. 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. 15. 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. 16. 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. 17. The sterilizable biodegradable fluid of claim 11 or 12 in which said metal is iron. 18. 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.degree. 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.sub.1 and R.sub.2, greater than or equal to about 10.sup.4 and 10.sup.5 M.sup.-1 sec.sup.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. 19. The composition of claim 1, 2, 11, 12, or 18 which is further characterized as being hypotonic. 20. The composition of claim 1, 2, 11, 12, or 18 which is further characterized as being isotonic. 21. 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. 22. 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. 23. 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. 24. The contrast agent of claim 21, 22 or 23 in which said metal oxide is associated with a macromolecular species. 25. The contrast agent of claim 24 in which said macromolecular species is a polysaccharide or mixtures thereof. 26. The contrast agent of claim 21, 22 or 23 in which said metal is iron. 27. The biodegradable superparamagnetic metal oxide of claim 2 in which said macromolecular species is a polysaccharide or mixtures thereof. 28. 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. 29. 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. 30. 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. 31. 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. 32. 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. 33. The contrast agent of claim 21, 22, 24 in which said metal is iron. 34. 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. 35. 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. 36. 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. 37. 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. 38. 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. 39. 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. 40. 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. 41. The contrast agent of claim 25 in which said metal is iron. 42. 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. 43. 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.