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US5262176A
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Synthesis of polysaccharide covered superparamagnetic oxide colloids
Assignee: Amag Pharmaceuticals Inc
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Filing: 1991-05-02
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Granted: 1993-11-16
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Expires: 2011-05-02
Abstract
Abstract In a method for the synthesis of a colloid including a superparamagnetic metal oxide coated with a polymer, an acidic solution of a metal salt and a polymer may be cooled, and then neutralized by the controlled addition of a cool solution of a base, and may then be converted, by the application of heat, to a homogenous superparamagnetic metal oxide colloid. According to a preferred embodiment, the polymer may be a polysaccharide. In a further embodiment of the invention, the polysaccharide may be dextran and the metal salt may be ferrous and ferric salts, which produces, according to the methods of the invention, a superparamagnetic iron oxide colloid with an extended plasma half-life.
Inventors
- 👤 Stephen Palmacci
- 👤 Lee Josephson
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 21:20
CPC Classifications
G; G01; G01R; G01R33/00; G01R33/20; G01R33/44; G01R33/48; G01R33/54; G01R33/56; G01R33/5601; A; A61; A61K; A61K49/00; A61K49/06; A61K49/18; A61K49/1806; A61K49/1809; A61K49/1818; A61K49/1821; A61K49/1824; A61K49/1827; A61K49/1851; A61K49/1863; A61L; A61L2/00; A61L2/02; A61L2/022; A61L2/025; B; B82; B82Y; B82Y5/00; C; C08; C08G; C08G18/00; C08G18/06; C08G18/08; C08G18/16; C08G18/18; C08G18/1808; C08G18/1816; C08G18/1825; C08G18/20; C08G18/2009; C08G18/2036; C08G18/22; C08G18/24; C08G18/244; C08G18/246; C08G18/26; C08J; C08J9/00; C08J9/04; C08J9/12; C08J9/14; C08J9/143; C08J9/144; A61L2103/00; A61L2103/05; C08G2101/00; C08J2375/00; C08J2375/04; Y; Y10; Y10T; Y10T428/00; Y10T428/29; Y10T428/2982; Y10T428/2991; Y10T428/2998
Claims Analysis
Total Claims: 46
Claim 1
Independent Claim
89 words
An improved method for obtaining an in vivo MR image of an organ or tissue of a human or animal subject, of the type including administering to such subject as a contrast agent to enhance such MR image an effective amount of a colloid including homogeneous superparamagnetic metal oxide particles dispersed in a physiologically acceptable carrier, wherein the colloid is synthesized by associating superparamagnetic metal oxide particles with a polymer in such a way that the polymer covers the superparamagnetic metal oxide particles and the polymer covering blocks opsominzation.
Claim 2
Dependent Claim
89 words
An improved method for obtaining an in vivo MR image of an organ or tissue of a human or animal subject, of the type including administering to such subject as a contrast agent to enhance such MR image an effective amount of a colloid including homogeneous superparamagnetic metal oxide particles dispersed in a physiologically acceptable carrier, wherein the colloid is synthesized by associating superparamagnetic metal oxide particles with a polymer in such a way that the polymer covers the superparamagnetic metal oxide particles and the polymer covering blocks opsominzation.
Claim 3
Dependent Claim
12 words
A method according to claim 1, wherein the polymer is a polysaccharide.
Claim 4
Dependent Claim
11 words
A method according to claim 1, further comprising crosslinking the polymer.
Claim 5
Dependent Claim
11 words
A method according to claim 2, further comprising crosslinking the polysaccharide.
Claim 6
Dependent Claim
40 words
A method according to claim 4, wherein the polysaccharide is dextran; and wherein the dextran is crosslinked with a crosslinking agent selected from the group consisting of epichorohydrin, glutaraldehyde, disuccinimydyl suberate, diethylenetriaminepentaacetic acid anhydride, cyanogen bromide, ethylchloroformate and divinyl sulfone.
Claim 7
Dependent Claim
11 words
A method according to claim 2, wherein the polysaccharide is dextran.
Claim 8
Dependent Claim
20 words
A method according to claim 6, wherein the colloid has a plasma half-life that is greater than approximately 20 minutes.
Claim 9
Dependent Claim
69 words
A method according to claim 1, wherein the synthesis of the colloid includes: (i) providing an acidic solution including a metal salt and the polymer; (ii) cooling the solution, obtained in step (i); (iii) neutralizing the solution, obtained in step (ii), by the controlled addition of a cool solution of a base; and (iv) heating the solution, obtained in step (iii), to obtain the homogenous superparamagnetic metal oxide colloid.
Claim 10
Dependent Claim
12 words
A method according to claim 8, wherein the polymer is a polysaccharide.
Claim 11
Dependent Claim
11 words
A method according to claim 9, wherein the polysaccharide is dextran.
Claim 12
Dependent Claim
86 words
A method according to claim 10, wherein the acidic solution, provided in step (i), includes a metal salt selected from the group consisting of (a) ferric salts; (b) ferrous salts; and (c) ferrous and ferric salts; wherein the ratio of the amount of dextran to the amount of metal salts, utilized in step (i), is approximately 10:1 by weight; and wherein the colloid, obtained in step (iv), is a superparamagnetic iron oxide colloid that includes a core consisting substantially of a single crystal of iron oxide.
Claim 13
Dependent Claim
88 words
A method according to claim 10, wherein the acidic solution, provided in step (i), includes a metal salt selected from the group consisting of (a) ferric salts; (b) ferrous salts; and (c) ferrous and ferric salts; wherein the ratio of the amount of dextran to the amount of metal salts, utilized in step (i), is approximately 4:1 by weight; and wherein the colloid, obtained in step (iv), is a superparamagnetic iron oxide colloid that includes a core consisting substantially of a range of 1-4 crystals of iron oxide.
Claim 14
Dependent Claim
20 words
A method according to claim 10, wherein the colloid has a plasma half-life that is greater than approximately 20 minutes.
Claim 15
Dependent Claim
15 words
A method according to claim 8, further comprising, after step (iv): (v) crosslinking the polymer.
Claim 16
Dependent Claim
15 words
A method according to claim 9, further comprising, after step (iv): (v) crosslinking the polysaccharide.
Claim 17
Dependent Claim
44 words
A method according to claim 15, wherein the polysaccharide is dextran; and wherein the step of crosslinking the dextran is performed with a crosslinking agent selected from the group consisting of epichorohydrin, glutaraldehyde, disuccinimydyl suberate, diethylenetriaminepentaacetic acid anhydride, cyanogen bromide, ethylchloroformate and divinyl sulfone.
Claim 18
Dependent Claim
32 words
A superparamagnetic metal oxide colloid comprising: a superparamagnetic metal oxide associated with a polymer in such a way that the polymer covers the superparamagnetic metal oxide and the polymer covering blocks opsominzation.
Claim 19
Dependent Claim
32 words
A superparamagnetic metal oxide colloid comprising: a superparamagnetic metal oxide associated with a polymer in such a way that the polymer covers the superparamagnetic metal oxide and the polymer covering blocks opsominzation.
Claim 20
Dependent Claim
12 words
A colloid according to claim 17, wherein the polymer is a polysaccharide.
Claim 21
Dependent Claim
11 words
A colloid according to claim 17, wherein the polymer is crosslinked.
Claim 22
Dependent Claim
11 words
A colloid according to claim 18, wherein the polysaccharide is crosslinked.
Claim 23
Dependent Claim
40 words
A colloid according to claim 20, wherein the polysaccharide is dextran; and wherein the dextran is crosslinked with a crosslinking agent selected from the group consisting of epichorohydrin, glutaraldehyde, disuccinimydyl suberate, diethylenetriaminepentaacetic acid anhydride, cyanogen bromide,, ethylchloroformate and divinyl sulfone.
Claim 24
Dependent Claim
67 words
A colloid according to claim 17, wherein the colloid is synthesized by: (i) providing an acidic solution including a metal salt and the polymer; (ii) cooling the solution, obtained in step (i); (iii) neutralizing the solution, obtained in step (ii), by the controlled addition of a cool solution of a base; and (iv) heating the solution, obtained in step (iii), to obtain the superparamagnetic metal oxide colloid.
Claim 25
Dependent Claim
12 words
A colloid according to claim 22, wherein the polymer, is a polysaccharide.
Claim 26
Dependent Claim
27 words
A colloid according to claim 23, wherein the polysaccharide is selected from the group consisting of arabinogalactan, dextran, hydroxyethyl starch, dextrin, mannan galactan, sulfated dextran and diethylaminodextran.
Claim 27
Dependent Claim
59 words
A colloid according to claim 22, wherein step (ii) includes the step of cooling the solution to between approximately 0° C. and approximately 12° C.; and wherein step (iv) includes the step of heating the solution to between approximately 60° C. and approximately 100° C., for not less than approximately 30 minutes, to obtain the superparamagnetic metal oxide colloid.
Claim 28
Dependent Claim
12 words
A colloid according to claim 25, wherein the polymer is a polysaccharide.
Claim 29
Dependent Claim
48 words
A colloid according to claim 26, wherein the acidic solution, provided in step (i), includes a metal salt selected from the group consisting of (a) ferric salts; (b) ferrous salts; and (c) ferrous and ferric salts; and wherein, in step (iv), a superparamagnetic iron oxide colloid is obtained.
Claim 30
Dependent Claim
27 words
A colloid according to claim 27, wherein the polysaccharide is selected from the group consisting of arabinogalactan, dextran, hydroxyethyl starch, dextrin, mannan, galactan, sulfated dextran and diethylaminodextran.
Claim 31
Dependent Claim
28 words
A colloid according to claim 26, wherein the colloid is capable of interacting with a cell receptor and undergoing receptor mediated endocytosis into a specific population of cells.
Claim 32
Dependent Claim
17 words
A colloid according to claim 29, wherein the polysaccharide is arabinogalactan and wherein the cells are hepatocytes.
Claim 33
Dependent Claim
17 words
A colloid according to claim 29, wherein the plasma clearance of the colloid is inhibited by asialoglycoproteins.
Claim 34
Dependent Claim
11 words
A colloid according to claim 26, wherein the polysaccharide is dextran.
Claim 35
Dependent Claim
20 words
A colloid according to claim 32, wherein the colloid has a plasma half-life that is greater than approximately 20 minutes.
Claim 36
Dependent Claim
54 words
A colloid according to claim 27, wherein the polysaccharide is dextran; wherein the ratio of the amount of dextran to the amount of metal salts, utilized in step (i), is approximately 10:1 by weight; and wherein the colloid, obtained in step (iv), includes a core consisting substantially of a single crystal of iron oxide.
Claim 37
Dependent Claim
56 words
A colloid according to claim 27, wherein the polysaccharide is dextran; wherein the ratio of the amount of dextran to the amount of metal salts, utilized in step (i), is approximately 4:1 by weight; and wherein the colloid, obtained in step (iv), includes a core consisting substantially of a range of 1-4 crystals of iron oxide.
Claim 38
Dependent Claim
14 words
A colloid according to claim 25, wherein the colloid is an MR contrast agent.
Claim 39
Dependent Claim
12 words
A colloid according to claim 36, wherein the polymer is a polysaccharide.
Claim 40
Dependent Claim
27 words
A colloid according to claim 37, wherein the polysaccharide is selected from the group consisting of arabinogalactan, dextran, hydroxyethyl starch, dextrin, mannan, galactan, sulfated dextran and diethylaminodextran.
Claim 41
Dependent Claim
21 words
A colloid according to claim 25, wherein the synthesis of the colloid further comprises, after step (iv): (v) crosslinking the polymer.
Claim 42
Dependent Claim
21 words
A colloid according to claim 26, wherein the synthesis of the colloid further comprises, after step (iv): (v) crosslinking the polysaccharide
Claim 43
Dependent Claim
42 words
A colloid according to claim 40, wherein the polysaccharide is dextran; and wherein the dextran is crosslinked with a crosslinking agent that is selected from the group consisting of epichorohydrin, glutaraldehyde, disuccinimydyl suberate, diethylenetriaminepentaacetic acid anhydride, cyanogen bromide, ethylchloroformate and divinyl sulfone.
Claim 44
Dependent Claim
14 words
A colloid according to claim 39, wherein the colloid is an MR contrast agent.
Claim 45
Dependent Claim
14 words
A colloid according to claim 40, wherein the colloid is an MR contrast agent.
Claim 46
Dependent Claim
14 words
A colloid according to claim 41, wherein the colloid is an MR contrast agent.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1996-11-15 | 1997-05-17 | 1997-11-16 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2000-11-15 | 2001-05-17 | 2001-11-16 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2004-11-15 | 2005-05-17 | 2005-11-16 | $7700.00 | Window Closed / Lapsed |