US2022211879A1PendingUtilityA1

Solvent free gadolinium contrast agents

Assignee: INVENTURE LLCPriority: Dec 29, 2016Filed: Mar 22, 2022Published: Jul 7, 2022

Est. expiryDec 29, 2036(~10.5 yrs left)· nominal 20-yr term from priority

Inventors:Richard Deslauriers Jonathan Balfour Michael Milbocker

A61K 49/18A61K 49/105A61K 2123/00A61K 49/101A61K 49/108A61K 49/106A61K 49/103A61K 49/1806

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Claims

Abstract

Disclosed herein are complexes of gadolinium metal, ligand and meglumine that are substantially free of non-aqueous solvents. In particular, solvent-free complexes of 1) gadopentetate dimeglumine and 2) gadoterate meglumine are disclosed and methods of their preparation are disclosed. In addition, methods are disclosed for purifying reactants, monitoring and controlling pH, quantifying the free gadolinium content, quantifying the concentration of gadolinium-ligand complex in aqueous solution, and procedures for producing a drug product in one step. The one step process eliminates the need to dry the gadolinium-ligand complex, which is typically highly hygroscopic. The one step process includes purification steps that do not require the use of non-aqueous solvents.

Claims

exact text as granted — not AI-modified

What is claimed is:

1 . An API for a gadolinium contrast agent that is suitable for injection in a mammal, the API comprising:
a complex of Gd(III) ion, ligand and meglumine in an aqueous formulation; wherein the aqueous formulation is produced by a solvent-free method so that the aqueous formulation comprises not more than 0.025% by weight of free ligand, the aqueous formulation comprises less than 1 part per million of free Gd(III) ion, and the aqueous formulation is substantially free of non-gadolinium and ligand complexes; and wherein API has a concentration that is in a range from 5 to 10 mg/ml of the aqueous formulation and a pH greater than 7.5.

2 . The API of claim 1 , wherein the formulation comprises less than 0.5 part per million of free Gd(III) ion.

3 . The API of claim 1 , wherein the formulation comprises less than 0.1 part per million of free Gd(III) ion.

4 . The API of claim 1 , wherein the formulation comprises less than 1 part per million of non-aqueous solvent.

5 . The API of claim 1 , wherein the formulation comprises less than 0.020% by weight of free ligand.

6 . The API of claim 1 , wherein the formulation comprises less than 50 parts per million of non-aqueous solvent.

7 . The API of claim 1 , wherein the ligand is DOTA.

8 . The API of claim 1 , wherein the complex is gadopentetate dimeglumine.

9 . The API of claim 1 , wherein the complex is gadoterate meglumine.

10 . The API of claim 1 , wherein the complex has a conditional thermodynamic stability constant, at pH 7.4, in the range of from about 18.1 to about 18.6.

11 . The API of claim 1 , wherein the gadolinium contrast agent has a pH in the range of from about 7.2 to about 7.5.

12 . The API of claim 1 , wherein the solvent free method comprises reacting and stirring the Gd(III) ion and ligand at a reaction temperature for at least about 12 hours and until there is no free Gd(III) ion to yield a Gd(III) ion and ligand complex of the formulation.

13 . The API of claim 12 , wherein the solvent free method further comprises: cooling the Gd(III) ion and ligand complex to 40-45° C., adding meglumine, and stirring at 40-45° C. for at least 1 hour to yield the formulation.

14 . The API of claim 12 , wherein the Gd(III) ion and ligand are reacted and stirred at a reaction temperature for at least about 24 hours.

15 . The API of claim 12 , wherein the Gd(III) ion and ligand are reacted and stirred at a reaction temperature for at least about 32 hours.

16 . A gadolinium contrast agent comprising a complex of Gd(III) ion, ligand and meglumine in an aqueous, wherein:
the gadolinium contrast agent is produced by a solvent-free method in which:
i) the Gd(III) ion and ligand are reacted and stirred at a reaction temperature for at least about 12 hours and until there is no free Gd(III) ion to yield a Gd(III) ion and ligand complex, and
ii) the Gd(III) ion and ligand complex are cooled to 40-45° C., meglumine is added, and stirring is performed at 40-45° C. for at least 1 hour to yield a concentrated API of the complex that has a pH &gt;7.5; and
iii) the concentrated API is diluted with water for injection to yield a formulation suitable for injection in a mammal;
wherein the formulation comprises not more than 0.025% by weight of free ligand; wherein the formulation comprises less than 1 part per million of free Gd(III) ion; and wherein the formulation is substantially free of non-gadolinium and ligand complexes.

17 . The gadolinium contrast agent of claim 22 , wherein the formulation comprises less than 0.5 part per million of free Gd(III) ion.

18 . The gadolinium contrast agent of claim 22 , wherein the formulation comprises less than 0.1 part per million of free Gd(III) ion.

19 . The gadolinium contrast agent of claim 22 , wherein the formulation comprises less than 1 part per million of non-aqueous solvent.

20 . The contrast agent of claim 22 , wherein the complex is gadopentetate dimeglumine or gadoterate meglumine.

21 . The contrast agent of claim 22 , wherein the formulation has a pH in the range of from about 7.2 to about 7.5.

22 . The contrast agent of claim 22 , wherein the complex has a conditional thermodynamic stability constant, at pH 7.4, in the range of from about 18.1 to about 18.6.

23 . The contrast agent of claim 22 , wherein the Gd(III) ion and ligand are reacted and stirred at a reaction temperature for at least about 24 hours.

24 . The contrast agent of claim 22 , wherein the ligand is DOTA.

25 . The contrast agent of claim 22 , wherein the formulation comprises less than 50 parts per million of non-aqueous solvent.

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