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 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: a) determination of a theoretical target concentration of free macrocyclic chelate C tcl in the final liquid pharmaceutical formulation; 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 cl and/or of free lanthanide C ll ; d) adjustment of C cl and/or of C ll so as to obtain C cl =C tcl and C ll =0.

1 . 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%, the said process comprising the following successive steps:
 a) determination of a theoretical target concentration of free macrocyclic chelate C tcl  in the final liquid pharmaceutical formulation;   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 cl  and/or of free lanthanide C ll ;   d) adjustment of C cl  and/or of C ll  so as to obtain C cl =C tcl  and C ll =0.   
     
     
         2 . Preparation process according to  claim 1 , characterized in that step b) consists in mixing a solution of free macrocyclic chelate and of free lanthanide so as to obtain complexation of the lanthanide by the macrocyclic chelate. 
     
     
         3 . Preparation process according to  claim 2 , characterized in that, in step b), there is a difference between the amounts of free macrocyclic chelate and of free lanthanide added and the stoichiometric proportions. 
     
     
         4 . Process according to  claim 3 , characterized in that the difference between the amounts of free macrocyclic chelate and of free lanthanide added and the stoichiometric proportions is such that the macrocyclic chelate/lanthanide or lanthanide/macrocyclic chelate mol/mol ratio is less than or equal to 1.4. 
     
     
         5 . Preparation process according to  claim 3 , characterized in that:
 in step b) the amounts of free macrocyclic chelate and of free lanthanide added are such that not all the lanthanide is complexed;   step c) consists in measuring C ll , C cl  being equal to 0;   step d) consists in adding to the formulation obtained in step b) the amount of free macrocyclic chelate necessary, firstly, to complete the complexation of the free lanthanide so as to obtain C ll =0, and, secondly, to obtain C cl =C tcl .   
     
     
         6 . Process according to  claim 5 , characterized in that, in step b), the lanthanide/macrocyclic chelate ratio (mol/mol) is less than 1.2. 
     
     
         7 . Preparation process according to  claim 3 , characterized in that:
 in step b), the amounts of free macrocyclic chelate and of free lanthanide added are such that all the lanthanide is complexed and that C cl >C tcl ;   step c) consists in measuring C cl , C ll  being equal to 0;   step d) consists in removing the appropriate amount of free macrocyclic chelate so as to obtain C cl =C tcl .   
     
     
         8 . Process according to  claim 7 , characterized in that, in step b), the macrocyclic chelate/lanthanide ratio (mol/mol) is less than 1.2. 
     
     
         9 . Preparation process according to  claim 1 , characterized in that:
 in step b), the amounts of free macrocyclic chelate and of free lanthanide added are equal to the stoichiometric proportions;   step c) consists in measuring C cl  and/or C ll ;   step d) consists in adding to the formulation obtained in step b) the amount of free macrocyclic chelate necessary, firstly, to complete, if necessary, the complexation of the free lanthanide and to obtain C ll =0, and, secondly, to obtain C cl =C tcl .   
     
     
         10 . Preparation process according to  claim 1 , characterized in that:
 in step b), the amounts of free macrocyclic chelate and of free lanthanide added are equal to the stoichiometric proportions;   it comprises between steps b) and c) an intermediate step b1) of modifying the pH of the pharmaceutical formulation obtained in step b) so as to shift the chemical equilibria in favour or in disfavour of complexation;   step c) is performed on the formulation obtained in step b1);   step d) consists in adjusting C cl  and/or C ll  so as to obtain C cl =C tcl  and C ll =0 by modifying the pH so as to shift the equilibrium in the direction opposite to that of step (b1) and optionally by adding or removing free macrocyclic chelate.   
     
     
         11 . Process according to  claim 10 , characterized in that:
 in step b), the mixing is performed at a pH of between 4 and 7,   step b1) consists in increasing the pH using a base up to a value of between 10 and 13,   step d) consists in lowering the pH down to a value of between 6.5 and 7.5, and optionally adding or removing free macrocyclic chelate.   
     
     
         12 . Process according to  claim 1 , characterized in that step b) consists in preparing a solid complex [chelate-lanthanide] and in dissolving it. 
     
     
         13 . Process according to  claim 1 , characterized in that the amount of calcium in the liquid pharmaceutical formulation administered to the patient is less than 50 ppm. 
     
     
         14 . Process according to  claim 13 , characterized in that it comprises, before step c), an intermediate step b2) of measuring the amount of calcium and, where appropriate, of removing the excess calcium. 
     
     
         15 . Process according to  claim 1 , characterized in that it comprises an additional step e) of checking C cl  and C ll . 
     
     
         16 . Process according to  claim 1 , characterized in that the macrocyclic chelate is advantageously chosen from DOTA, NOTA, DOTAGA, DO3A, BT-DO3A, HP-DO3A and PCTA. 
     
     
         17 . Process according to  claim 16 , characterized in that the macrocyclic chelate is DOTA. 
     
     
         18 . Process according to  claim 17 , characterized in that the pharmaceutical formulation is a pharmaceutical formulation of meglumine salt of the DOTA-gadolinium complex. 
     
     
         19 . Process according to  claim 1 , characterized in that an agent for blocking the free lanthanide is added in step b). 
     
     
         20 . Process according to  claim 19 , characterized in that the agent for blocking the free lanthanide is a polycarboxylic acid. 
     
     
         21 . Pharmaceutical formulation that may be obtained via a process according to  claim 1 , characterized in that it contains between 0.002 and 0.4 mol/mol % of free macrocyclic chelate. 
     
     
         22 . Formulation according to  claim 21 , characterized in that the free macrocyclic chelate is free DOTA. 
     
     
         23 . Formulation according to  claim 21 , characterized in that it contains between 0.02 and 0.3 mol/mol % of free macrocyclic chelate. 
     
     
         24 . Formulation according to  claim 21 , characterized in that it contains between 0.025 and 0.25 mol/mol % of free macrocyclic chelate. 
     
     
         25 . Formulation according to  claim 22 , characterized in that it contains between 0.02 and 0.08 mol/mol % of free DOTA. 
     
     
         26 . Formulation according to  claim 22 , characterized in that it contains between 0.15 and 0.25 mol/mol % of free DOTA. 
     
     
         27 . Formulation according to  claim 21 , characterized in that its calcium content is less than 50 ppm. 
     
     
         28 . Formulation according to  claim 27 , characterized in that its calcium content is less than 20 ppm. 
     
     
         29 . Formulation according to  claim 28 , characterized in that its calcium content is less than 5 ppm. 
     
     
         30 . Process according to  claim 13 , characterized in that the amount of calcium in the liquid pharmaceutical formulation administered to the patient is less than 20 ppm. 
     
     
         31 . Process according to  claim 30 , characterized in that the amount of calcium in the liquid pharmaceutical formulation administered to the patient is less than 5 ppm.