Claims for Patent: 4,337,240

Summary for Patent: 4,337,240

Title:	Denatured albumin complexes for radioscintigraphic imaging and evaluation of reticuloendothelial systems
Abstract:	Small sized material (less than 0.2 .mu.m, preferably less than 0.1 .mu.m) comprising a complex of (1) denatured albumin, particularly human serum albumin and (2) a metal reducing agent, particularly a stannous reducing agent, preferably formed in the presence of a stabilizing ligand, which complex, when labelled with technetium-99m provides an excellent agent for imaging or otherwise evaluating reticuloendothelial systems (RES) and/or components thereof, particularly the bone marrow, liver and/or lymphatic system; methods of making and using the same; a complex (physical or chemical) of technetium-99m with such materials and methods of using such latter complex.
Inventor(s):	Saklad; Eugene L. (Sudbury, MA)
Assignee:	New England Nuclear Corporation (Boston, MA)
Application Number:	06/018,312
Patent Claims:	1. A composition for labelling with .sup.99m Tc for radioactive imaging comprising complexes of denatured albumin and a reducing metal, at least a major portion of which having a particle size of less than about 0.2 .mu.m. 2. A composition according to claim 1, said composition also comprising an additional stabilizing ligand for said reducing metal. 3. A composition according to claim 2, said ligand being selected from the group consisting of a phosphonate, a phosphate, an aminocarboxylate, a polyhydroxycarboxylate and a polycarboxylate. 4. A composition according to claim 3, said reducing metal comprising a stannous reducing metal. 5. A composition according to claim 2, at least 90% of said complexes being not greater than about 0.1 .mu.m in particle size. 6. A composition according to claim 5, at least 90% of said complexes being about 0.004 to 0.1 .mu.m in particle size. 7. A composition according to claim 5, at least 85% of said complexes being about 0.01 to 0.08 .mu.m in particle size. 8. A composition according to claim 7, said reducing metal comprising a stannous reducing metal and said ligand being a diphosphonate. 9. A composition according to claim 2, said ligand being a diphosphonate. 10. A composition according to claim 2, said albumin being human serum albumin and said reducing metal being a stannous reducing metal. 11. A composition according to claim 10 stabilized with undenatured albumin and a buffer. 12. A composition according to claim 11 further comprising a non-ionic surfactant. 13. A composition according to claim 10, said composition being in the form of a freeze-dried solid. 14. A composition according to claim 10, said albumin having been denatured by application of heat at a pH differing from the apparent isoelectric point of said albumin in said composition by about 1.5 to 4 pH units. 15. A composition according to claim 14, the pH at denaturation differing from the apparent isoelectric point of said albumin by about 2 to 3.5 pH units. 16. A composition according to claim 14, said albumin having been denatured at about 80.degree.-100.degree. C. 17. A composition according to claim 10, said albumin having been denatured by application of heat at a pH of about 6.5 to 11. 18. A composition according to claim 17, said albumin having been denatured at a pH of about 7.5 to 9.5, and at a temperature of about 80.degree.-100.degree. C. 19. A composition according to claim 1, said albumin being human serum albumin, said reducing metal being a stannous reducing metal, said composition being stabilized with undenatured human serum albumin and a buffer, said complexes being denatured at a pH of about 7.5 to 9.5, and said composition being freeze-dried. 20. A radioactive imaging agent comprising .sup.99m Tc-labelled complexes of denatured albumin and a reducing metal, at least a major portion of said complexes having a particle size of less than about 0.2 .mu.m. 21. An agent according to claim 20 further comprising a stabilizing ligand for said reducing metal. 22. An agent according to claim 21 said albumin being human serum albumin, said reducing metal comprising a stannous reducing metal, and said ligand being selected from the group consisting of phosphonates, phosphates, aminocarboxylates, polyhydroxycarboxylates and polycarboxylates. 23. An agent according to claim 21, said ligand being a diphosphonate. 24. An agent according to claim 23, said ligand being hydroxyethylene diphosphonate. 25. An agent according to claim 23, said ligand being methylene diphosphonate. 26. An agent according to claim 21, at least 90% of said microaggregates having a particle size not greater than 0.2 .mu.m. 27. An agent according to claim 26, at least about 85% of said complexes having a particle size of about 0.01 to 0.08 .mu.m. 28. An agent according to claim 21, further comprising undenatured albumin, a buffer and surfactant. 29. An agent according to claim 20, said albumin being human serum albumin, said reducing metal being a stannous, reducing metal, at least 90% of said complexes having a particle size of between about 0.01 and 0.08 .mu.m. 30. An agent according to claim 20, stabilized with undenatured human serum albumin and a buffer, said complexes being denatured at a pH differing from the apparent isoelectric point of the albumin in the composition by about 1.5 to 4 pH units. 31. An agent according to claim 30, said pH at denaturation being between about 7.5 and 9.5. 32. An agent according to claim 30, said pH at denaturation being between about 1.0 and 4.5 33. A method for making an agent for labelling with .sup.99m Tc for radioactive imaging, said method comprising denaturing albumin in the presence of a reducing metal to form reducing metal/denatured albumin complexes, at least the major part of said complexes having a particle size of less than about 0.2 .mu.m. 34. A method according to claim 33, said denaturation being carried out in the presence of a stabilizing ligand for said reducing metal. 35. A method according to claim 34, said albumin being human serum albumin, said reducing metal being Sn.sup.++ and said ligand being selected from the group consisting of a phosphonate, a phosphate, an aminocarboxylate, a polyhydroxycarboxylate and a polycarboxylate. 36. A method according to claim 35, said denaturation being carried out at a pH at which at least about 85% have a particle size between 0.01 and 0.08 .mu.m. 37. A method according to claim 34, said denaturation being carried out at a pH at which at least 90% of the complexes have a particle size not greater than 0.2 .mu.m. 38. A method according to claim 37, said denaturation being carried out at a pH which differs from the apparent isoelectric point of the albumin in the composition by about 1.5 to 4 pH units. 39. A method according to claim 38, said denaturation being carried out at a pH on the alkaline side of the apparent isoelectric point of said albumin. 40. A method according to claim 38, said denaturation being carried out on the acid side of the apparent isoelectric point of said albumin. 41. A method according to claim 34, said ligand being a diphosphonate. 42. A method according to claim 41, said ligand being hydroxyethylene diphosphonate. 43. A method according to claim 41, said ligand being methylene diphosphonate. 44. A method according to claim 43, said denaturation being carried out by heating at a pH of between about 7.5 and 9.5, at which at least 90% of the complexes have a particle size not greater than 0.2 .mu.m and at least 85% have a particle size between about 0.01 and 0.08 .mu.m, said reducing metal being a stannous reducing metal, and said albumin being human serum albumin. 45. A method according to claim 33, said denaturation being carried out by heating albumin and said reducing metal by microwave heating. 46. A method according to claim 33, said denaturation being carried out by heating albumin and said reducing metal by induction heating. 47. A method of evaluating at least one element of the reticuloendothelial system of a primate, comprising injecting into the primate a composition comprising .sup.99m Tc labelled reducing metal/denatured albumin complexes at least a major portion of which have a particle size of less than about 0.2 .mu.m, to concentrate said .sup.99m Tc-labelled complexes in the reticuloendothelial system. 48. A method according to claim 47, said composition further comprising a stabilizing ligand for said reducing metal. 49. A method according to claim 48, said reducing metal being a stannous reducing metal and said ligand being a diphosphonate. 50. A method according to claim 47, at least 90% of said complexes having a particle size not greater than 0.1 .mu.m and at least a majority of said complexes having a particle size between 0.01 and 0.08 .mu.m. 51. A method of imaging bone marrow in a primate, comprising injecting into the primate a composition comprising .sup.99m Tc-labelled reducing agent/denatured albumin complexes to concentrate said .sup.99m Tc-labelled complexes in the bone marrow. 52. The method of claim 51, wherein at least 90% of the labelled reducing agent/denatured albumin complexes have a particle size below about 0.2 .mu.m, and the composition further comprises a stabilizing ligand for said reducing agent. 53. The method of claim 52, wherein the reducing agent is stannous, the denatured albumin is denatured human serum albumin, the stabilizing ligand is a diphosphonate, and at least 85% of the reducing agent/denatured albumin has a particle size of between about 0.01 and 0.08 .mu.m. 54. A method of imaging at least one component of the lymphatic system in a mammal, comprising injecting into the mammal a composition comprising .sup.99m Tc-labelled reducing agent/denatured albumin complexes to concentrate said .sup.99m Tc-labelled complexes in the aforementioned components of the lymphatic system. 55. The method of claim 54, wherein at least 90% of the labelled reducing agent/denatured albumin complexes have a particle size below about 0.2 .mu.m, and the composition further comprises a stabilizing ligand for said reducing metal. 56. The method of claim 55, wherein the reducing agent is stannous, the denatured albumin is denatured human serum albumin, the stabilizing ligand is a diphosphonate, and at least 85% of the reducing agent/denatured albumin has a particle size of between about 0.01 and 0.08 .mu.m. 57. A method of evaluating the rate of clearance of particulate material from the blood of a mammal, comprising injecting into the mammal a composition comprising .sup.99m Tc-labelled reducing agent/denatured albumin complexes, and measuring the rate of clearance of said complexes from said blood over a period of time. 58. The method of claim 57, wherein at least 90% of the labelled reducing agent/denatured albumin complexes have a particle size below about 0.2 .mu.m, and the composition further comprises a stabilizing ligand for said reducing metal. 59. The method of claim 58, wherein the reducing agent is stannous, the denatured albumin is denatured human serum albumin, the stabilizing ligand is a diphosphonate, and at least 85% of the reducing agent/denatured albumin has a particle size of between about 0.01 and 0.08 .mu.m. 60. A composition according to claim 1, said albumin having been denatured at a pH between about 1.0 and 4.5.

Details for Patent 4,337,240

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	ALBUKED, PLASBUMIN-20, PLASBUMIN-25, PLASBUMIN-5	albumin (human)	For Injection	101138	10/21/1942		1998-04-20
Baxalta Us Inc.	BUMINATE, FLEXBUMIN	albumin (human)	Injection	101452	03/03/1954		1998-04-20
Csl Behring Ag	ALBURX	albumin (human)	Injection	102366	07/23/1976		1998-04-20
Grifols Biologicals Llc	ALBUTEIN	albumin (human)	Injection	102478	08/15/1978		1998-04-20