Process for preparing a pharmaceutical formulation of contrast agents

Inventors

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

Assignees

Guerbet SA

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 tch1 and C lan1=0, wherein C t ch1 is the target concentration of free macrocyclic chelate in the final liquid pharmaceutical formulation.

Core Innovation

The invention relates to 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%, while driving free lanthanide to substantially zero. The process prepares a formulation containing both a complexed species and free lanthanide and optionally free macrocyclic chelate, and then controls the free species by measuring and adjusting concentrations.

A central aspect is that the process mixing step uses a defined lanthanide/macrocyclic chelate mol/mol ratio, followed by pH adjustments and analytical measurement of free lanthanide concentration. After adjusting the pH of a sample to set free macrocyclic chelate concentration C_ch1 to 0, the concentration of free lanthanide C_lan1 is measured, and free macrocyclic chelate is added to complete the complexation of the free lanthanide to obtain C_lan1 = 0 and the target concentration C_ch1 = C_tch1 between 0.002% and 0.4%.

The document specifies that the pH of the final liquid pharmaceutical formulation is adjusted with meglumine, and that the complex of macrocyclic chelate with a lanthanide is the meglumine salt of the DOTA-gadolinium complex with DOTA as the macrocyclic chelate and gadolinium as the lanthanide. The operating steps (b) and (d) occur in the same reactor, and the liquid pharmaceutical formulation is an injectable solution.

Claims Coverage

The partial content includes two independent claims, both centered on an industrial process that sets a controlled low level of free macrocyclic chelate between 0.002% and 0.4% while achieving C_lan1 = 0 by sequential mixing, pH adjustment, measuring free lanthanide, and adding free macrocyclic chelate, with the final formulation being an injectable solution and with specified identity for the DOTA-gadolinium meglumine complex.

Both independent claims provide an industrial process that mixes free macrocyclic chelate with free lanthanide at a defined mol/mol ratio, uses pH adjustment and measurement to determine free lanthanide, and then adds free macrocyclic chelate to reach C_lan1 = 0 while setting the final free chelate concentration C_ch1 to between 0.002% and 0.4%, with final pH adjustment using meglumine and with the specified DOTA-gadolinium meglumine complex and same-reactor operation for mixing and addition; one claim further specifies time, temperature, and pH constraints for mixing and a final pH range.

Stated Advantages

Documented Applications