| 摘要 |
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%, said process comprising the following successive steps:
b) preparation of a liquid pharmaceutical composition containing the complex of macrocyclic chelate with a lanthanide, free macrocyclic chelate that is not under the form of an excipient X[X',L] in which L is the macrocyclic chelate and X and X' are a metal ion, in particular chosen independently from calcium, sodium, zinc and magnesium, and/or free lanthanide,
by mixing a solution of free macrocyclic chelate and of free lanthanide, so as to obtain complexation of the lanthanide by the macrocyclic chelate, the amounts of free macrocyclic chelate and of free lanthanide being such that all the lanthanide is complexed and that C ch 1 > Ct ch 1 , wherein C ch 1 is the concentration of free macrocyclic chelate and C t ch 1 is the target concentration of the free macrocyclic chelate in the final liquid pharmaceutical formulation and is selected in the range of between 0.002 % and 0.4 % mol/mol;
c) measurement in the pharmaceutical formulation obtained in step b) of C ch 1 , the concentration of free lanthanide C lan 1 being equal to 0;
d) adjustment of C ch 1 and of C lan 1 so as to obtain C ch 1 = C t ch 1 and C lan 1 = 0 by adding to the formulation obtained in step b) free lanthanide,
wherein Ct ch 1 is the target concentration of the free macrocyclic chelate in the final liquid pharmaceutical formulation and is selected in the range of 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 in the final liquid pharmaceutical formulation. |
