Details for Patent: 9,555,133

Title:	Polyol and polyether iron oxide complexes as pharmacological and/or MRI contrast agents
Abstract:	Iron oxide complexes, pharmacological compositions and unit dosage thereof, and methods for their administration, of the type employing an iron oxide complex with a polyol, are disclosed. The pharmacological compositions employ a polysaccharide iron oxide complex, wherein the polysaccharide is a modified polyol such as a carboxyalkylated reduced dextran. The complex is stable to terminal sterilization by autoclaving. The compositions are suitable for parenteral administration to a subject for the treatment of iron deficiencies or as MRI contrast agent. The complex is substantially immunosilent, provide minimal anaphylaxis and undergo minimal dissolution in vivo. The pharmacological compositions of the complex contain minimal free iron which can be quantified by a variety of methods.
Inventor(s):	Groman; Ernest V. (Brookline, MA), Paul; Kenneth G. (Holliston, MA), Frigo; Timothy B. (Waltham, MA), Bengele; Howard (Canton, MA), Lewis; Jerome M. (Newton, MA)
Assignee:	AMAG Pharmaceuticals, Inc. (Waltham, MA)
Filing Date:	Jul 09, 2013
Application Number:	13/937,923
Claims:	1. A method of making an autoclavable carboxymethylated reduced dextran iron oxide complex intended for administration by injection to a mammalian subject, the method comprising the steps of: (i) reacting a dextran with a borohydride salt, or hydrogen in the presence of a hydrogenation catalyst, to produce a reduced dextran; (ii) carboxymethylating the reduced dextran to produce a carboxymethylated reduced dextran; (iii) complexing the carboxymethylated reduced dextran with an iron salt to produce a carboxymethylated reduced dextran iron oxide complex; and (iv) sterilizing the carboxymethylated reduced dextran iron oxide complex by autoclaving; the complexing comprising contacting the carboxymethylated reduced dextran with a mixture of ferric and ferrous salts, cooling the resulting solution and adding ammonium hydroxide to neutralize the solution and recovering the carboxymethylated reduced dextran iron oxide complex; such complex being stable at a temperature of at least about 121.degree. C. for a period effective to sterilize the complex; wherein the autoclavable carboxymethylated reduced dextran iron oxide complex has a particle size of 10 nm to 50 nm. 2. The method of claim 1, wherein the carboxymethylated reduced dextran is produced at a temperature of less than about 40.degree. C. 3. The method of claim 1, wherein the contacting is performed in an acidic solution. 4. The method of claim 1, wherein the carboxymethylated reduced dextran iron oxide complex is stable at about 121.degree. C. for 30 minutes. 5. The method of claim 4, wherein the carboxymethylated reduced dextran iron oxide complex is stable at 121.degree. C. for 30 minutes at neutral pH. 6. A method of making an autoclavable carboxymethylated reduced dextran iron oxide complex intended for administration by injection to a mammalian subject, the method comprising the steps of: (i) reacting a dextran with a borohydride salt, or hydrogen in the presence of a hydrogenation catalyst, to produce a reduced dextran; (ii) carboxymethylating the reduced dextran to produce a carboxymethylated reduced dextran; (iii) complexing the carboxymethylated reduced dextran with an iron salt to produce a carboxymethylated reduced dextran iron oxide complex; and (iv) sterilizing the carboxymethylated reduced dextran iron oxide complex by autoclaving; the complexing comprising contacting the carboxymethylated reduced dextran with a mixture of ferric and ferrous salts, cooling the resulting solution and adding ammonium hydroxide to neutralize the solution and recovering the carboxymethylated reduced dextran iron oxide complex; such complex being stable at a temperature of at least about 121.degree. C. for a period effective to sterilize the complex; wherein the carboxymethylated reduced dextran comprises at least about 1100 micromoles of carboxyl groups per gram and less than about 1500 micromoles of carboxyl groups per gram; and wherein the carboxymethylated reduced dextran iron oxide complex has a particle size of 10 nm to 50 nm. 7. The method of claim 6, wherein the carboxymethylated reduced dextran is produced at a temperature of less than about 40.degree. C. 8. The method of claim 6, wherein the contacting is performed in an acidic solution. 9. The method of claim 6, wherein the carboxymethylated reduced dextran iron oxide complex is stable at about 121.degree. C. for 30 minutes. 10. The method of claim 9, wherein the carboxymethylated reduced dextran iron oxide complex is stable at 121.degree. C. for 30 minutes at neutral pH. 11. A method of making an autoclavable carboxymethylated reduced dextran iron oxide complex intended for administration by injection to a mammalian subject, the method comprising the steps of: (i) reacting a dextran with a borohydride salt, or hydrogen in the presence of a hydrogenation catalyst, to produce a reduced dextran; (ii) carboxymethylating the reduced dextran to produce a carboxymethylated reduced dextran; (iii) complexing the carboxymethylated reduced dextran with an iron salt to produce a carboxymethylated reduced dextran iron oxide complex; and (iv) sterilizing the carboxymethylated reduced dextran iron oxide complex by autoclaving; the complexing comprising contacting the carboxymethylated reduced dextran with a mixture of ferric and ferrous salts, cooling the resulting solution and adding ammonium hydroxide to neutralize the solution and recovering the carboxymethylated reduced dextran iron oxide complex; such complex being stable at a temperature of at least about 121.degree. C. for 30 minutes; wherein the reduced dextran has an average molecular weight of about 10 kDa; wherein the complex has a particle size of 10 nm to 50 nm; and the carboxymethylated reduced dextran comprises at least about 1100 micromoles of carboxyl groups per gram and less than about 1500 micromoles of carboxyl groups per gram. 12. The method of claim 11, wherein the carboxymethylated reduced dextran is produced at a temperature of less than about 40.degree. C. 13. The method of claim 11, wherein the contacting is performed in an acidic solution. 14. The method of claim 11, wherein the carboxymethylated reduced dextran iron oxide complex is stable at 121.degree. C. for 30 minutes at neutral pH.