Polyol and Polyether Iron Oxide Complexes as Pharmacological and/or MRI Contrast Agents

• US 20110144054A1
• Filed: 12/08/2010
• Published: 06/16/2011
• Est. Priority Date: 04/09/1999
• Status: Active Grant

• Current Assignee: AMAG Pharmaceuticals, Inc. (Apollo Global Management, Inc.)
• Original Assignee: AMAG Pharmaceuticals, Inc. (Apollo Global Management, Inc.)
• Inventors: Bengele, Howard, Paul, Kenneth G., Groman, Ernest V., Lewis, Jerome M., Frigo, Timothy B.
• Granted Patent: US 8,501,158 B2
• Time in Patent Office: Days
• US Class Current: 514/59
• CPC Class Codes: A61K 31/721 Dextrans
• CPC Class Codes: A61K 33/26 Iron; Compounds thereof
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/6923 the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 47/6929 the form being a nanoparticle, e.g. an immuno-nanoparticle
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 49/186 the organic macromolecular compound being polyethyleneglycol [PEG]
• CPC Class Codes: A61K 49/1863 the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Pharmacological compositions, and methods for administration, of the type employing an iron oxide complex with a polyol or polyether. The methods of administration may comprise parenteral administration of an effective dose of the complex formulated in a biocompatible liquid delivered at a rate of from about 1 mL/sec to less than 1 mL/min and wherein upon administration the complex provides minimal detectable free iron in a subject, and minimal incidence of anaphylaxis. The pharmacological compositions are of the type employing a polyol or polyether iron oxide complex, which, upon parenteral administration to a subject, are substantially immunosilent, provide minimal anaphylaxis and minimal free iron, and undergo minimal dissolution in vivo.

Claims

1. An improved method for administration of a pharmacological composition of the type employing an iron oxide complex with a polyol, wherein the improvement comprises:

administering parenterally an effective dose of a terminally sterilizable reduced derivatized polyol iron oxide complex composition prepared in a total volume of biocompatible liquid from about 1 mL to about 15 mL and for a total single dose from about 50 mg to about 600 mg of iron, so that upon administration the complex provides minimal detectable free iron in a subject, and minimal incidence of anaphylaxis; and

effecting such administration at a rate substantially greater than 1 mL/min.

2. A method for administration according to claim 1, further comprising effecting administration at a rate of about 1 mL/sec.

3. An improved method for administration of a pharmacological composition according to claim 1, wherein the complex is formulated in a biocompatible liquid so that upon administration it provides minimal dissolution of the complex in a human subject.

4. An improved method for administration of a pharmacological composition according to claim 3, wherein the complex is formulated in a biocompatible liquid so that upon administration the complex is substantially immunosilent in a human subject.

5. An improved method for administration of a pharmacological composition according to claim 1, wherein the terminally sterilizable reduced derivatized polyol iron oxide complex is carboxyalkylated.

6. An improved method for administration of a pharmacological composition according to claim 5, wherein the polyol is a polysaccharide.

7. An improved method for administration of a pharmacological composition according to claim 6, wherein the carboxyalkylated terminally sterilizable reduced derivatized polyol iron oxide complex is a carboxymethylated terminally sterilizable reduced derivatized polyol iron oxide complex.

8. An improved method for administration of a pharmacological composition according to claim 7, wherein the carboxyalkylated terminally sterilizable reduced derivatized polyol iron oxide complex is reduced carboxymethylated.dextran.

9. A method of treating a subject with an iron oxide complex, the method comprising:

parenterally administering a terminally sterilizable reduced derivatized polyol iron oxide complex formulated in a pharmaceutically acceptable formulation in a biocompatible liquid;

effecting administration at a rate substantially greater than 1 mL/min; and

providing an effective dose in the range of about 1 mg/kg of body weight to about 4 mg/kg of body weight in a total volume of biocompatible liquid of between about 1 mL and 15 mL so that minimal free iron and minimal anaphylaxis occurs.

10. A method of treating a subject with an iron oxide complex according to claim 9, wherein the terminally sterilizable reduced derivatized polyol iron oxide complex is carboxyalkylated.

14. A method according to claim 9, further comprising providing an effective dose so that minimal dissolution of the complex occurs in the subject.

15. A method according to claim 14, further comprising providing an effective dose so that the complex is substantially immuno silent to the subject.

11. A method of treating a subject with an iron oxide complex according to claim 11, wherein the polyol is a polysaccharide.

12. A method of treating a subject with an iron oxide complex according to claim 11, wherein the carboxyalkylated terminally sterilizable reduced derivatized polyol complex is a carboxymethylated terminally sterilizable reduced derivatized polyol complex.

13. A method of treating a subject with an iron oxide complex according to claim 12, wherein the carboxyalkylated terminally sterilizable reduced derivatized polyol iron oxide complex is reduced carboxymethylated.dextran.