Process for preparing a pharmaceutical formulation of contrast agents

Patent metadata

Field	Value
Publication number	US-9636427-B2
Application number	US-201615140077-A
Country	US
Kind code	B2
Filing date	Apr 27, 2016
Priority date	Feb 19, 2008
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

The invention relates to a process for preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide and a mol/mol amount of free macrocyclic chelate of between 0.002% and 0.4%, advantageously between 0.02% and 0.3% and very advantageously between 0.025% and 0.25%, the macrocyclic chelate advantageously being chosen from DOTA, NOTA, DOTAGA, DO3A, BT-DO3A, HP-DO3A and PCTA, and is preferably DOTA, the said process comprising the following successive steps: b) preparation of a liquid pharmaceutical composition containing, firstly, the complex of macrocyclic chelate with a lanthanide, and, secondly, free macrocyclic chelate and/or free lanthanide; c) measurement in the pharmaceutical formulation obtained in step b) of the concentration of free macrocyclic chelate C ch1 and/or of free lanthanide C lan1 ; d) adjustment of C ch1 and/or of C lan1 so as to obtain C ch1 =C t ch1 and C lan1 =0, wherein C t ch1 is the target concentration of free macrocyclic chelate in the final liquid pharmaceutical formulation.

First claim

The invention claimed is:

1. An industrial process for preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide and a mol/mol amount of free macrocyclic chelate between 0.002% and 0.4%, said process comprising the following successive steps:
b) preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide, and:
free macrocyclic chelate,
and optionally free lanthanide;
said step b) consisting of mixing a solution of free macrocyclic chelate and of free lanthanide, the amounts of free macrocyclic chelate and of free lanthanide being such that the macrocyclic chelate/lanthanide mol/mol ratio is between 1.001 and 1.3,

c1) adjusting the pH of a sample of the liquid pharmaceutical formulation obtained in step b) so that the concentration of free lanthanide C lan 1 is equal to 0;
c2) measuring, in the sample of the liquid pharmaceutical formulation obtained in step c1), the concentration of free macrocyclic chelate C ch 1 ;
d) adjusting C ch 1 and C lan 1 in the liquid pharmaceutical formulation obtained in step b) so as to obtain C ch 1 =C t ch 1 and C lan 1 =0 based on the measurements obtained in step c2),
by adding free lanthanide to the liquid pharmaceutical formulation obtained in step b) if C ch 1 >C t ch 1 , or
by adding further free macrocyclic chelate if C ch 1 <C t ch 1 ,
C t ch 1 representing the target concentration of the free macrocyclic chelate in the final liquid pharmaceutical formulation, C t ch 1 being between 0.002% and 0.4% mol/mol;

wherein the amount of free macrocyclic chelate in the final liquid pharmaceutical formulation corresponds to the proportion of free macrocyclic chelate relative to the amount of complexed macrocyclic chelate DOTA-Gd in the final liquid pharmaceutical formulation in mol/mol,
wherein the macrocyclic chelate is DOTA and the lanthanide is gadolinium,
and wherein steps b) and d) of the process occur in the same reactor, and
wherein the liquid pharmaceutical formulation is an injectable solution.

2. The process of claim 1 , wherein the mol/mol amount of free macrocyclic chelate is between 0.025% and 0.25%.

3. The process of claim 1 , wherein the liquid pharmaceutical formulation is a liquid pharmaceutical formulation of the meglumine salt of a DOTA-gadolinium complex.

4. The process of claim 3 , wherein the adjustment step (d) comprises at the end a step of adjustment of the pH and of the volume.

5. The process of claim 4 , wherein the pH is adjusted with meglumine.

6. The process of claim 1 , wherein step (b) is carried out at a temperature of between 60° C. and 100° C.

7. The process of claim 1 , wherein step (b) is carried out at 80° C.

8. The process of claim 1 , wherein in step (b) the amounts of free macrocyclic chelate and of free lanthanide added are such that the macrocyclic chelate/lanthanide ratio (mol/mol) is between 1.005 and 1.2.

9. The process of claim 1 , wherein any calcium present in the final liquid pharmaceutical formulation is present in an amount of less than 50 ppm.

10. The process of claim 9 , wherein the amount of calcium present in the final liquid pharmaceutical formulation is less than 20 ppm.

11. The process of claim 10 , wherein the amount of calcium present in the final liquid pharmaceutical formulation is less than 5 ppm.

12. The process of claim 3 , wherein the amount of calcium in the free DOTA, water, and meglumine used in steps b) and d) is less than 50 ppm.

13. The process of claim 9 , wherein it comprises, before step c1), an intermediate step (b2) of measuring the amount of calcium in the obtained solution, and removing any excess calcium in order to obtain an amount of less than 50 ppm in said solution.

14. The process of claim 1 , wherein it comprises an additional step e) of checking C ch 1 and C lan 1 .

15. The process of claim 1 , wherein step (b) is carried out at a temperature between 60° C. and 100° C. and in that the liquid pharmaceutical formulation is then cooled before the adjustment step (d).

16. The process of claim 1 , wherein gadolinium is added as gadolinium oxide in step (b).

17. The process of claim 1 , wherein said step b) consists of mixing a solution of free macrocyclic chelate and free lanthanide for 1 to 3 hours at a pH between 4 and 7.

18. An industrial process for preparing an injectable liquid pharmaceutical formulation containing a complex of DOTA with gadolinium and a mol/mol amount of free DOTA between 0.002% and 0.4%, said process comprising the following successive steps:
b) preparing a liquid pharmaceutical formulation containing a complex of DOTA with gadolinium, and:
free DOTA,
and optionally free gadolinium;
said step b) consisting of mixing a solution of free DOTA and of free gadolinium, the amounts of free DOTA and of free gadolinium being such that the DOTA/gadolinium mol/mol ratio is between 1.001 and 1.3,

c1) adjusting the pH of a sample of the liquid pharmaceutical formulation obtained in step b) to 7;
c2) measuring, in the sample of the liquid pharmaceutical formulation obtained in step c1), the concentration of free macrocyclic chelate C ch 1 ;
d) adjusting C ch 1 and C lan 1 in the liquid pharmaceutical formulation obtained in step b) so as to obtain C ch 1 =C t ch 1 and C lan 1 =0 based on the measurements obtained in step c2),
if C ch 1 >C t ch 1 , by adding free gadolinium to the liquid pharmaceutical formulation obtained in step b),
if C ch 1 <C t ch 1 , by adding further free DOTA in order to obtain C ch 1 =C t ch 1 ,
C t ch 1 representing the target concentration of the free DOTA in the final liquid pharmaceutical formulation, C t ch 1 being between 0.002% and 0.4% mol/mol;

wherein the amount of free DOTA in the final liquid pharmaceutical formulation corresponds to the proportion of free DOTA relative to the amount of complex DOTA-Gd in the final liquid pharmaceutical formulation in mol/mol.

19. The process of claim 18 , wherein said step b) consists of mixing a solution of free DOTA and free gadolinium for 1 to 3 hours at a pH of between 4 and 7 and at a temperature between 60° C. and 100° C.

20. The process of claim 1 , wherein in step c1), the pH is adjusted to 7.

Assignees

• Guerbet Sa

Inventors

• Meyer Dominique
• Corot Claire
• Port Marc
• Barbotin Vincent
• Bonnemain Bruno

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• G01N33/15

  Medicinal preparations {; Physical properties thereof, e.g. dissolubility} · CPC title

• A61K9/0019

  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 title

• A61K31/28

  Compounds containing heavy metals · CPC title

• A61K49/108 Primary

  the metal complex being Gd-DOTA · CPC title