Pharmaceutical compositions of Gd-based contrast agents
The present invention relates to pharmaceutical compositions comprising an gadolinium-complex and a saturated macrocyclic tetraamine that find application in diagnostic imaging as diagnostic agents, in particular as contrast agents having improved tolerability, specifically in Magnetic Resonance Imaging (MRI), and to their preparation.
1 . A pharmaceutical composition comprising a gadolinium complex, a C 12 -C 16 saturated tetraazamacrocycle, and a pharmaceutically acceptable carrier, galenic diluent or excipient, wherein an amount of the gadolinium complex is in the form of salt (1:1) with the C 12 -C 16 saturated tetraazamacrocycle, and a remaining amount of the gadolinium complex is in the form of a pharmaceutically acceptable salt with a cation of (i) an inorganic base selected from an alkali and alkaline-earth metal, (ii) an organic base selected from ethanolamine, diethanolamine, morpholine, glucamine, N-methylglucamine, and N,N-dimethylglucamine or (iii) an amino acid selected from lysine, arginine and ornithine.
2 . The pharmaceutical composition according to claim 1 wherein the gadolinium complex is with a chelating ligand selected from the group consisting of: diethylenetriamine pentaacetic acid; ethoxybenzyl diethylenetriamine pentaacetic acid; and (4RS)-[4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oic acid].
3 . The pharmaceutical composition according to claim 1 wherein the tetraazamacrocycle is Cyclen or Cyclam.
4 . The pharmaceutical composition according to claim 3 wherein the tetraazamacrocycle is Cyclen.
5 . The pharmaceutical composition according to claim 4 wherein the Gd-complex is Gd-BOPTA.
6 . The pharmaceutical composition according to claim 5 wherein from 1 to 50% by mole of the Gd-BOPTA is in the form of a salt (1:1) with Cyclen.
7 . The pharmaceutical composition according to claim 5 comprising Gd-BOPTA salt (1:1) with Cyclen, Gd-BOPTA salt with N-methylglucamine, and one or more pharmaceutically acceptable carriers, galenic diluents and excipients.
8 . The pharmaceutical composition according to claim 7 wherein the amount of the Gd-BOPTA salt with Cyclen is from 1% to 30% by moles relative to the total Gd-BOPTA amount.
9 . The pharmaceutical composition according to claim 8 wherein the amount of the Gd-BOPTA salt (1:1) with Cyclen is from 1% to 20% by moles relative to the total Gd-BOPTA amount.
10 . The pharmaceutical composition according to claim 1 wherein the Gd-complex is Gd-BOPTA.