US4226846A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Albumin microaggregates for radioactive scanning of reticuloendothelial systems
Assignee: Bristol Myers Squibb Pharma Co
•
Filing: 1978-04-20
•
Granted: 1980-10-07
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Expires: 1998-04-20
Abstract
Abstract Microaggregates of a complex of (1) 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 reticuloendothelial systems (RES), particularly the liver, spleen, and bone marrow; methods of making and using the same; a complex (physical or chemical) of technetium-99m with such microaggregates and methods of using such latter complex.
Inventors
- 👤 Eugene L. Saklad
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-28 12:40
CPC Classifications
A; A61; A61K; A61K51/00; A61K51/12; A61K51/1217; A61K51/02; A61K51/04; A61K51/08; A61K51/081; A61K51/1241; A61K51/1255; A61K2123/00
Claims Analysis
Total Claims: 79
Claim 1
Independent Claim
17 words
A composition for labelling with Tc-99m for radioactive imaging comprising microaggregates of albumin and a reducing metal.
Claim 2
Dependent Claim
17 words
A composition for labelling with Tc-99m for radioactive imaging comprising microaggregates of albumin and a reducing metal.
Claim 3
Dependent Claim
18 words
A composition according to claim 1, said composition also comprising an additional stabilizing ligand for said reducing metal.
Claim 4
Dependent Claim
46 words
A composition for labelling with Tc-99m for radioactive imaging comprising microaggregates of albumin and a reducing metal, said composition also comprising an additional stabilizing ligand for said reducing metal selected from the group consisting of a phosphonate, a phosphate, an aminocarboxylate, a polyhydroxycarboxylate and a polycarboxylate.
Claim 5
Dependent Claim
46 words
A composition for labelling with Tc-99m for radioactive imaging comprising microaggregates of albumin and a reducing metal, said composition also comprising an additional stabilizing ligand for said reducing metal selected from the group consisting of a phosphonate, a phosphate, an aminocarboxylate, a polyhydroxycarboxylate and a polycarboxylate.
Claim 6
Dependent Claim
18 words
A composition according to claim 3, said reducing metal being Sn ++ and said ligand being a diphosphonate.
Claim 7
Dependent Claim
21 words
A composition according to claim 2, at least 90% of said microaggregates being not greater than 5 μm in particle size.
Claim 8
Dependent Claim
21 words
A composition according to claim 5, at least 40% of said microaggregates being between 0.2 and 5 μm in particle size.
Claim 9
Dependent Claim
18 words
A composition according to claim 5, at least 40% of said microaggregates being between 0.2 and 3 μm.
Claim 10
Dependent Claim
29 words
A composition according to claim 7, said reducing metal being stannous and at least the major portion of said microaggregates being between 0.2 and 3 μm in particle size.
Claim 11
Dependent Claim
21 words
A composition according to claim 5, no more than 50% of said microaggregates being less than 0.2 μm in particle size.
Claim 12
Dependent Claim
18 words
A composition according to claim 2, said albumin being human serum albumin and said reducing metal being stannous.
Claim 13
Dependent Claim
17 words
A composition according to claim 10 wherein said composition is stabilized with undenatured albumin and a buffer.
Claim 14
Dependent Claim
11 words
A composition according to claim 11 also containing a non-ionic surfactant.
Claim 15
Dependent Claim
27 words
A composition according to claim 10, microaggregated at a pH between 4.5 and 9.5 but on the alkaline side of the apparent isoelectric point of said albumin.
Claim 16
Dependent Claim
13 words
A composition according to claim 13, said pH being between 5.4 and 7.0.
Claim 17
Dependent Claim
16 words
A composition according to claim 10, said composition being in the form of a freeze-dried solid.
Claim 18
Dependent Claim
21 words
A composition according to claim 1, at least 90% of said microaggregates being not greater than 5 μm in particle size.
Claim 19
Dependent Claim
48 words
A composition for labelling with Tc-99m for radioactive imaging comprising microaggregates of albumin and a reducing metal, at least 90% of said microaggregates being not greater than 5 μm in particle size, and at least 40% of said microaggregates being between 0.2 and 5 μm in particle size.
Claim 20
Dependent Claim
48 words
A composition for labelling with Tc-99m for radioactive imaging comprising microaggregates of albumin and a reducing metal, at least 90% of said microaggregates being not greater than 5 μm in particle size, and at least 40% of said microaggregates being between 0.2 and 5 μm in particle size.
Claim 21
Dependent Claim
21 words
A composition according to claim 17, no more than 50% of said microaggregates being less than 0.2 μm in particle size.
Claim 22
Dependent Claim
44 words
A composition according to claim 1, said albumin being human serum albumin, said reducing metal being stannous, said microaggregates being microaggregated at a pH of 3.5-9.5, said composition being stabilized with undenatured human serum albumin and a buffer, and said stabilized composition being freeze-dried.
Claim 23
Dependent Claim
43 words
A radioactive imaging agent comprising Tc-99m labelled microaggregates of albumin and a reducing metal, wherein at least 90% of said microaggregates have a particle size not greater than 5 μm and at least 40% of said microaggregates are between 0.2 and 5 μm.
Claim 24
Dependent Claim
43 words
A radioactive imaging agent comprising Tc-99m labelled microaggregates of albumin and a reducing metal, wherein at least 90% of said microaggregates have a particle size not greater than 5 μm and at least 40% of said microaggregates are between 0.2 and 5 μm.
Claim 25
Dependent Claim
15 words
An agent according to claim 20 also comprising a stabilizing ligand for said reducing metal.
Claim 26
Dependent Claim
40 words
A radioactive imaging agent comprising Tc-99m labelled microaggregates of human serum albumin and a stannous reducing metal, said agent also comprising a stabilizing ligand for said reducing metal selected from the group consisting of phosphonates, phosphates, aminocarboxylates, polyhydroxycarboxylates and polycarboxylates.
Claim 27
Dependent Claim
40 words
A radioactive imaging agent comprising Tc-99m labelled microaggregates of human serum albumin and a stannous reducing metal, said agent also comprising a stabilizing ligand for said reducing metal selected from the group consisting of phosphonates, phosphates, aminocarboxylates, polyhydroxycarboxylates and polycarboxylates.
Claim 28
Dependent Claim
26 words
A radioactive imaging agent comprising Tc-99m labelled microaggregates of albumin and a reducing metal, said agent also comprising a diphosphonate stabilizing ligand for said reducing metal.
Claim 29
Dependent Claim
26 words
A radioactive imaging agent comprising Tc-99m labelled microaggregates of albumin and a reducing metal, said agent also comprising a diphosphonate stabilizing ligand for said reducing metal.
Claim 30
Dependent Claim
11 words
An agent according to claim 23, said ligand being hydroxyethylene diphosphonate.
Claim 31
Dependent Claim
11 words
An agent according to claim 23, said ligand being methylene diphosphonate.
Claim 32
Dependent Claim
19 words
An agent according to claim 22, not substantially more than 50% of said microaggregates being less than 0.2 μm.
Claim 33
Dependent Claim
18 words
An agent according to claim 21, at least 40% of said microaggregates being between 0.2 and 3 μm.
Claim 34
Dependent Claim
18 words
An agent according to claim 21, the major portion of said microaggregates being between 0.2 and 3.0 μm.
Claim 35
Dependent Claim
13 words
An agent according to claim 21, admixed with non-aggregated albumin, buffer and surfactant.
Claim 36
Dependent Claim
46 words
An agent according to claim 20, said albumin being human serum albumin, said reducing metal being stannous, at least 90% of said microaggregates having a particle size no greater than 5 μm and not substantially more than 50% of said microaggregates being less than 0.2 μm.
Claim 37
Dependent Claim
78 words
A radioactive imaging agent comprising Tc-99m labelled microaggregates of human serum albumin and a stannous reducing metal, at least 90% of said microaggregates having a particle size no greater than 5 μm and not substantially more than 50% of said microaggregates being less than 0.2 μm, said agent stabilized with non-aggregated human serum albumin and buffer, said microaggregates being microaggregated at a pH of 4.5-9.5 but on the alkaline side of the apparent isoelectric point of said albumin.
Claim 38
Dependent Claim
78 words
A radioactive imaging agent comprising Tc-99m labelled microaggregates of human serum albumin and a stannous reducing metal, at least 90% of said microaggregates having a particle size no greater than 5 μm and not substantially more than 50% of said microaggregates being less than 0.2 μm, said agent stabilized with non-aggregated human serum albumin and buffer, said microaggregates being microaggregated at a pH of 4.5-9.5 but on the alkaline side of the apparent isoelectric point of said albumin.
Claim 39
Dependent Claim
13 words
An agent according to claim 31, said pH being between 5.4 and 7.0.
Claim 40
Dependent Claim
19 words
An agent according to claim 31, said agent comprising methylene diphosphonate and said pH being between 5.6 and 6.5.
Claim 41
Independent Claim
25 words
A method for making an agent for labelling with Tc-99m for radioactive imaging, said method comprising microaggregating albumin in the presence of a reducing metal.
Claim 42
Independent Claim
25 words
A method for making an agent for labelling with Tc-99m for radioactive imaging, said method comprising microaggregating albumin in the presence of a reducing metal.
Claim 43
Dependent Claim
22 words
A method according to claim 34, said microaggregation being carried out in the presence of a stabilizing ligand for said reducing metal.
Claim 44
Independent Claim
61 words
A method for making an agent for labelling with Tc-99m for radioactive imaging, said method comprising microaggregating human serum albumin in the presence of a stannous reducing metal, said microaggregation being carried out in the presence of a stabilizing ligand for said reducing metal selected from the group consisting of a phosphonate, a phosphate, an aminocarboxylate, a polyhydroxycarboxylate and a polycarboxylate.
Claim 45
Independent Claim
61 words
A method for making an agent for labelling with Tc-99m for radioactive imaging, said method comprising microaggregating human serum albumin in the presence of a stannous reducing metal, said microaggregation being carried out in the presence of a stabilizing ligand for said reducing metal selected from the group consisting of a phosphonate, a phosphate, an aminocarboxylate, a polyhydroxycarboxylate and a polycarboxylate.
Claim 46
Dependent Claim
31 words
A method according to claim 35, said microaggregation being carried out at a pH at which at least 90% of the microaggregates have a particle size not greater than 5 μm.
Claim 47
Dependent Claim
31 words
A method according to claim 37, said microaggregation being carried out at a pH at which not substantially more than 50% of the microaggregates have a particle size below 0.2 μm.
Claim 48
Dependent Claim
28 words
A method according to claim 37, said aggregation being carried out at a pH at which at least 40% have a particle size between 0.2 and 5 μm.
Claim 49
Dependent Claim
31 words
A method according to claim 37, said aggregation being carried out at a pH at which at least 40% of the microaggregates have a particle size between 0.2 and 3 μm.
Claim 50
Dependent Claim
33 words
A method according to claim 37, said aggregation being carried out at a pH at which at least the major portion of the microaggregates have a particle size between 0.2 and 3 μm.
Claim 51
Dependent Claim
31 words
A method according to claim 35, said aggregation being carried out at a pH between 4.5 and 9.5 but on the alkaline side of the apparent isoelectric point of said albumin.
Claim 52
Dependent Claim
13 words
A method according to claim 42, said pH being between 5.4 and 7.0.
Claim 53
Dependent Claim
11 words
A method according to claim 36, said ligand being a diphosphonate.
Claim 54
Dependent Claim
11 words
A method according to claim 36, said ligand being hydroxyethylene diphosphonate.
Claim 55
Dependent Claim
11 words
A method according to claim 36, said ligand being methylene diphosphonate.
Claim 56
Dependent Claim
62 words
A method according to claim 46, said microaggregates being carried out by heating at a pH of 5.4 to 6.6, at which at least 90% of the microaggregates have a particle size not greater than 5 μm and at least 40% have a particle size between 0.2 and 3 μm, said reducing metal being stannous and said albumin being human serum albumin.
Claim 57
Dependent Claim
36 words
A method according to claim 34, said microaggregation being carried out by passing a solution of undenatured human serum albumin and said reducing metal through a plurality of sequentially arranged heat exchangers in a semi-continuous manner.
Claim 58
Dependent Claim
56 words
A method according to claim 34, said reducing metal being stannous and said albumin being human serum albumin, said aggregation being carried out at a pH at which at least 90% of the microaggregates have a particle size not greater than 5 μm and not substantially more than 50% have a particle size below 0.2 μm.
Claim 59
Dependent Claim
53 words
A method according to claim 49, said microaggregation being carried out by heating at a pH between 4.5 and 9.5 but on the alkaline side of the apparent isoelectric point of said albumin at which at least the major portion of said microaggregates have a particle size between 0.2 μm and 3.0 μm.
Claim 60
Dependent Claim
13 words
A method according to claim 50, said pH being between 5.4 and 7.0.
Claim 61
Dependent Claim
13 words
A method according to claim 50, said pH being between 5.4 and 6.6
Claim 62
Dependent Claim
21 words
A method according to claim 34, said aggregation being carried out by heating albumin and said reducing metal by radiofrequency heating.
Claim 63
Dependent Claim
21 words
A method according to claim 34, said aggregation being carried out by heating albumin and said reducing metal by microwave heating.
Claim 64
Dependent Claim
21 words
A method according to claim 34, said aggregation being carried out by heating albumin and said reducing metal by induction heating.
Claim 65
Independent Claim
30 words
A method of imaging the RES of a primate comprising injecting into the primate Tc-99m-labelled microaggregates of HSA and a reducing metal to concentrate said Tc-99m-labelled microaggregates in the RES.
Claim 66
Independent Claim
30 words
A method of imaging the RES of a primate comprising injecting into the primate Tc-99m-labelled microaggregates of HSA and a reducing metal to concentrate said Tc-99m-labelled microaggregates in the RES.
Claim 67
Dependent Claim
16 words
A method according to claim 56, said composition containing a stabilizing ligand for said reducing metal.
Claim 68
Independent Claim
45 words
A method for imaging the RES of a primate comprising injecting into the primate a composition comprising Tc-99m-labelled microaggregates of HSA and a stannous reducing metal to concentrate said Tc-99m-labelled microaggregates in the RES, said composition containing a diphosphonate stabilizing ligand for said reducing metal.
Claim 69
Independent Claim
45 words
A method for imaging the RES of a primate comprising injecting into the primate a composition comprising Tc-99m-labelled microaggregates of HSA and a stannous reducing metal to concentrate said Tc-99m-labelled microaggregates in the RES, said composition containing a diphosphonate stabilizing ligand for said reducing metal.
Claim 70
Dependent Claim
34 words
A method according to claim 58, at least 90% of said microaggregates having a particle size not greater than 5 μm and at least 40% have a particle size between 0.2 and 3 μm.
Claim 71
Dependent Claim
106 words
A preaggregated bulk, containing human serum albumin to be aggregated to microaggregates for radioactive labelling for use as an RES imaging agent, comprising a solution of unaggregated and undenatured human serum albumin, reducing metal and stabilizing ligand for said reducing metal, said bulk having a pH of between 4.5 and 9.5 but on the alkaline side of the isoelectric point of said albumin, the amount of ligand being sufficient to stabilize said stannous ions and prevent precipitation thereof before microaggregation but insufficient to provide any substantial non-RES target seeking properties when the microaggregates subsequently formed from said bulk are radioactively labelled and utilized for RES imaging.
Claim 72
Dependent Claim
106 words
A preaggregated bulk, containing human serum albumin to be aggregated to microaggregates for radioactive labelling for use as an RES imaging agent, comprising a solution of unaggregated and undenatured human serum albumin, reducing metal and stabilizing ligand for said reducing metal, said bulk having a pH of between 4.5 and 9.5 but on the alkaline side of the isoelectric point of said albumin, the amount of ligand being sufficient to stabilize said stannous ions and prevent precipitation thereof before microaggregation but insufficient to provide any substantial non-RES target seeking properties when the microaggregates subsequently formed from said bulk are radioactively labelled and utilized for RES imaging.
Claim 73
Dependent Claim
13 words
A bulk according to claim 60, said pH being between 5.4 and 7.0.
Claim 74
Dependent Claim
11 words
A bulk according to claim 61, said reducing metal being stannous.
Claim 75
Dependent Claim
123 words
A preaggregated bulk containing human serum albumin to be aggregated to microaggregates for radioactive labelling for use as an RES imaging agent, comprising a solution of unaggregated and undenatured human serum albumin, stannous reducing metal and stabilizing ligand for said reducing metal, said bulk having a pH of between 5.6 and 6.5 but on the alkaline side of the isoelectric point of said albumin, the amount of ligand being sufficient to stabilize said stannous ions and prevent precipitation thereof before microaggregation but insufficient to provide any substantial non-RES target seeking properties when the microaggregates subsequently formed from said bulk are radioactively labelled and utilized for RES imaging, said ligand being a diphosphonate selected from the group consisting of methylene diphosphonate and hydroxyethylene diphosphonate.
Claim 76
Dependent Claim
123 words
A preaggregated bulk containing human serum albumin to be aggregated to microaggregates for radioactive labelling for use as an RES imaging agent, comprising a solution of unaggregated and undenatured human serum albumin, stannous reducing metal and stabilizing ligand for said reducing metal, said bulk having a pH of between 5.6 and 6.5 but on the alkaline side of the isoelectric point of said albumin, the amount of ligand being sufficient to stabilize said stannous ions and prevent precipitation thereof before microaggregation but insufficient to provide any substantial non-RES target seeking properties when the microaggregates subsequently formed from said bulk are radioactively labelled and utilized for RES imaging, said ligand being a diphosphonate selected from the group consisting of methylene diphosphonate and hydroxyethylene diphosphonate.
Claim 77
Independent Claim
45 words
A method for making an agent for labelling with Tc-99m for radioactive imaging, said method comprising microaggregating albumin in the presence of a reducing metal, at a pH between 3.5 and 9.5 but at a pH away from the apparent isoelectric point of said albumin.
Claim 78
Independent Claim
45 words
A method for making an agent for labelling with Tc-99m for radioactive imaging, said method comprising microaggregating albumin in the presence of a reducing metal, at a pH between 3.5 and 9.5 but at a pH away from the apparent isoelectric point of said albumin.
Claim 79
Dependent Claim
69 words
A method according to claim 64 wherein said reducing metal is stannous and said albumin is human serum albumin, said step of microaggregating comprising heating said albumin and said reducing agent at said pH, thus forming microaggregates at least a major portion of which have a particle size between 0.2 μm and 5.0 μm, and at least 90% of which have a particle size not greater than 5.0 μm.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1983-10-07 | 1984-04-07 | 1984-10-07 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1987-10-07 | 1988-04-07 | 1988-10-07 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1991-10-07 | 1992-04-07 | 1992-10-07 | $7700.00 | Window Closed / Lapsed |