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Claims for Patent: 4,827,945

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Claims for Patent: 4,827,945

Title: Biologically degradable superparamagnetic materials for use in clinical applications
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.
Inventor(s): Groman; Ernest V. (Brookline, MA), Josephson; Lee (Arlington, MA), Lewis; Jerome M. (Newton, MA)
Assignee: Advanced Magnetics, Incorporated (Cambridge, MA)
Application Number:07/067,586
Patent Claims: 1. 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.degree. 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.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; (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.

2. 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.degree. 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.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; (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.

3. 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.degree. 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.sub.1 an R.sub.2, greater than or equal to about 10.sup.4 and 10.sup.5 M.sup.-1 sec.sup.-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.

4. 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.

5. 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.

6. The method of claim 2 wherein the polymeric substance is selected from the group consisting of polysacharides, carbohydrates, polypeptides, organosilanes, proteins, and composites thereof.

7. The method of claim 2 wherein the polymeric substance consists of dextran having a molecular weight between 5,000 and 250,000 daltons.

8. The method of claim 2 wherein the polymeric substance is albumin.

9. The method of claim 2 wherein the polymeric substance is a polymer of N-2-aminoethyl-3-aminopropyltrimethoxysilane.

10. The method of claim 3 wherein said superparamagnetic fluid is administered to the subject by intravascular injection.

11. 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.

12. The method of claim 3 wherein the organ or tissue imaged is part of the reticuloendothelial system.

13. The method of claim 3 wherein the organ or tissue imaged is selected from the group consisting of a liver, spleen, and bone marrow.

14. The method of claim 3 wherein the organ or tissue imaged is part of the lymphatic system.

15. The method of claim 3 wherein the organ or tissue imaged is a lymph node.

16. The method of claim 3 wherein the organ or tissue imaged is part of the nervous system.

17. 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.

18. The method of claim 3 wherein the organ or tissue imaged is part of the vascular compartment.

19. The method of claim 3 wherein the organ or tissue imaged is selected from the group consisting of blood capillaries and lymph vessels.

20. The method of claim 3 wherein the organ or tissue imaged is a lung.

21. The method of claim 3 wherein the organ or tissue imaged is a part of the gastrointestinal tract.

22. 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.

23. 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.

24. The method of claim 23 wherein the biological molecule is an antibody.

25. The method of claim 24 wherein the antibody is an anti-melanoma antibody and the tissue being imaged is melanoma tissue.

26. The method of claim 24 wherein the antibody is an anti-heart myosin antibody and the tissue being imaged is infarcted heart tissue.

27. The method of claim 24 wherein the antibody is an anti-T-cell antibody and the tissue being imaged is lymphoma tissue.

28. The method of claim 24 wherein the antibody is anti-carcinomic embryonic antigens and the tissue being imaged is colonic tumor tissue.

29. The method of claim 24 wherein the antibody is an anti-ovarian cancer cell antibody and the tissue being imaged is ovarian cancer tissue.

30. The method of claim 23 wherein the biological molecule is a carbohydrate.

31. The method of claim 23 wherein the biological molecule is a hormone.

32. 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.

33. The method of claim 32 wherein the blocking agent is paramagnetic.

34. The method of claim 32 wherein the contrast agent is a biodegradable superparamagnetic iron oxide and the blocking agent is a paramagnetic iron oxide.

35. 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.

36. The method of claim 35 wherein the blocking agent is paramagnetic.

37. 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.

38. 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.sup.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.

39. 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.degree. 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.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; (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.

40. The method of claim 3 wherein said superparamagnetic fluid is administered to the subject parenterally.
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