Process for preparing a pharmaceutical formulation of contrast agents

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 offree 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.

1 . 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%, and with a calcium content is less than 50 ppm, obtainable by a process comprising the following successive steps:
 a) preparing a liquid pharmaceutical composition containing, firstly, the complex of macrocyclic chelate with a lanthanide, and, secondly:   free macrocyclic chelate,   and/or free lanthanide;   b) measurement in the pharmaceutical formulation obtained in step a) of the concentration of free macrocyclic chelate C ch 1  and/or of free lanthanide C lan 1 ;   c) adjustment of C ch 1  and/or of C lan 1  so as to obtain   C ch 1 =C t ch 1  and C lan 1 =0, wherein C t ch 1  is the target concentration of the free macrocyclic chelate in the final liquid pharmaceutical formulation and is of between 0.002% and 0.4% mol/mol,   wherein the amount of free macrocyclic chelate in the liquid pharmaceutical formulation corresponds to the proportion of free macrocyclic chelate relative to the amount of complexed macrocyclic chelate in the liquid pharmaceutical formulation.   
     
     
         2 . Formulation according to  claim 1 , wherein the macrocyclic chelate is selected from the group consisting of DOTA, NOTA, DOTAGA, DO3A, BT-DO3A, HP-DO3A and PCTA. 
     
     
         3 . Formulation according to  claim 2 , wherein the macrocyclic chelate is DOTA. 
     
     
         4 . Formulation according to  claim 3 , wherein the pharmaceutical formulation is a pharmaceutical formulation of meglumine salt of the DOTA-gadolinium complex. 
     
     
         5 . Formulation according to  claim 1 , wherein it contains between 0.02 and 0.3 mol/mol % of free macrocyclic chelate. 
     
     
         6 . Formulation according to  claim 1 , wherein it contains between 0.025 and 0.25 mol/mol % of free macrocyclic chelate. 
     
     
         7 . Formulation according to  claim 3 , wherein the formulation contains between 0.02 and 0.08 mol/mol % of free DOTA. 
     
     
         8 . Formulation according to  claim 1 , wherein the formulation contains between 0.15 and 0.25 mol/mol % of free DOTA. 
     
     
         9 . Formulation according to  claim 1 , wherein its calcium content is less than 20 ppm. 
     
     
         10 . Formulation according to  claim 9 , wherein its calcium content is less than 5 ppm. 
     
     
         11 . Formulation according to  claim 1 , further comprising or co-administered with a supplementary compound capable of coordinating free lanthanide selected from the group consisting of mono or polycarboxylic acids or hydroxyacids. 
     
     
         12 . Formulation according to  claim 1 , further comprising an anti-fibrosis agent selected from the group consisting of steroids, anti-inflammatories, vitamins.