Method for preparing a pharmaceutical formulation of lanthanide chelate in powder form

摘要

The present invention relates to a method for preparing a pharmaceutical formulation of lanthanide chelate in powder form, wherein the powder constitutes a mol/mol excess of free chelate of between 0.002 and 0.4%.

主权项

1. A method for preparing a pharmaceutical formulation of a macrocyclic chelate of a lanthanide, wherein the macrocyclic chelate is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA), the lanthanide is gadolinium (Gd), and the macrocyclic chelate of a lanthanide is a DOTA-Gd complex, said method comprising the following successive steps of:
(1) mixing in a solution a macrocyclic chelate and a lanthanide so as to obtain a complexation solution of the lanthanide by the macrocyclic chelate, the complexation solution comprising, in addition to the macrocyclic chelate-lanthanide complex, an excess amount X1 of free macrocyclic chelate, wherein a step (1) is carried out in a single step or in several successive steps by measuring and adjusting, so as to have an amount X1 of free macrocyclic chelate, and the step (1) comprises the following successive substeps of:
(1.1) complexing in solution the lanthanide with the macrocyclic chelate(1.2) measuring the macrocyclic chelate and/or the lanthanide that is free(1.3) adding free macrocyclic chelate, as to complex the free lanthanide if any remains at the end of step (1.1), and to obtain an amount X1 of free macrocyclic chelate; (2) optionally measuring X1 and/or adjusting X1 so as to have X1 between 0.002 and 0.4% mol/mol; (3) precipitating or crystallizing the complexation solution obtained in step (1) at a pH in the range 1 to 9 from an organic solvent and at a temperature in the range 0° C. to 80° C., wherein said solvent is employed at a volume ratio to the complexation solution in the range 10:1 to 20:1, so as to obtain a powder of the macrocyclic chelate-lanthanide complex, said powder containing an excess amount X2 of free macrocyclic chelate, wherein X2 represents the amount of free macrocyclic chelate obtained after precipitation or crystallization and X2 is less than X1, (4) adjusting X2 by adding free macrocyclic chelate so as to obtain:
(4.a) X2 between 0.002 and 0.4% mol/mol, and(4.b) X2 corresponding to between 0.2 and 0.95 times X1,wherein said powder obtained after step (4) comprises a mol/mol excess of free macrocyclic chelate of between 0.002 and 0.4%; and
(5) returning said powder to solution so as to form a pharmaceutical composition in liquid form, said pharmaceutical composition in liquid form being ready for administration to a patient.