Formulation of contrast media and process of preparation thereof
AssigneesBayer Aktiengesellschaft, Bayer Pharma Aktiengesellschaft
InventorsStephan Holzschuh, Thomas Frenzel, Gregor Jost, Jessica Lohrke, Wolfgang Ebert, Thomas Brumby, Wolfgang Halfbrodt
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Abstract
The present disclosure relates to a liquid pharmaceutical formulation comprising a DO3A-derived tetra-chelate of formula (I), in which M is an ion of a paramagnetic metal, preferably a Gd3+ ion, and R1, R2, R3, R4 and R5 are as defined in the claims, in a pharmaceutical acceptable solvent. The present disclosure also relates to a method of preparation of said liquid pharmaceutical formulation and to a method of imaging involving said liquid pharmaceutical formulation.
Claims14
A liquid pharmaceutical formulation comprising:
- a DO3A-derived tetra-chelate having a general formula selected from the chelates of formulae (I-a), (I-b), and (I-c):
- or a stereoisomer, a tautomer or a salt thereof, or a mixture of same in a range of from 70 to 700 mmol of Gd3+ ion/L;
- a compound capable of forming a chelate with a free gadolinium metal ion Gd3+ comprising Ca-BT-DO3A (Calcobutrol) in a range of 0.002% to 5% mol/mol (inclusive) measured as a proportion relative to a total Gd3+ concentration in the liquid pharmaceutical formulation;
- a buffer in the form of 10.0 mmol/L Trometamol (TRIS, 2-amino-2-(hydroxymethyl) propane-1,3-diol);
- an isotonicity agent in the form of NaCl;
- a pH adjusting agent in the form of 0.1 N HCI (aq);
- and
- a pharmaceutically acceptable solvent in the form of water.
A liquid pharmaceutical formulation comprising:
- a DO3A-derived tetra-chelate having a general formula I-a
- or a stereoisomer, a tautomer or a salt thereof, or a mixture of same in a range of from 70 to 700 mmol of Gd3+ ion/L;
- a compound capable of forming a chelate with a free gadolinium metal ion Gd3+ comprising Ca-BT-DO3A (Calcobutrol) in a range of 0.002% to 5% mol/mol (inclusive) measured as a proportion relative to a total Gd3+ concentration in the liquid pharmaceutical formulation;
- a buffer in the form of 10.0 mmol/L Trometamol (TRIS, 2-amino-2-(hydroxymethyl)propane-1,3-diol) and a buffer pH adjusting agent present in an amount sufficient to provide a pH in the range of 7.6 to 8.2;
- an isotonicity agent in the form of NaCl present in an amount sufficient to provide an osmolality in a range of 250 to 350 mOsm/Kg (inclusive);
- a pH adjusting agent in the form of HCI (aq.) present in an amount sufficient to adjust a pH of the liquid pharmaceutical formulation to a pH in a range of 6.9 to 7.9;
- and
- a pharmaceutically acceptable solvent in the form of water present in an amount sufficient to provide a final concentration of the liquid pharmaceutical formulation having the range of 70 to 700 mmol of Gd3+ ion/L.
A method for making a liquid pharmaceutical formulation, the method comprising:
- providing a sufficient volume of a pharmaceutically acceptable solvent in the form of water;
- dissolving Trometamol (TRIS, 2-amino-2-(hydroxymethyl) propane-1,3-diol) buffer in an amount to produce a 10.0 mmol/L buffered solution and adjusting a pH of the buffered solution to a pH in a range of 7.6 to 8.2 (inclusive) by addition of a 0.1 N solution of HCI (aq);
- dissolving an amount of Ca-BT-DO3A (Calcobutrol) in the buffered solution to provide a 0.1% mol/mol concentration of the Ca-BT-DO3A measured as a proportion relative to a total Gd3+concentration in the liquid pharmaceutical formulation;
- dissolving an amount of a DO3A-derived tetra-chelate having a general formula I-a
- or a stereoisomer, a tautomer or a salt thereof, or a mixture of same in an amount sufficient to provide from 70 to 700 mmol of Gd3+ ion/L in the liquid pharmaceutical formulation;
- dissolving sodium chloride as an isotonicity agent in an amount sufficient to provide an osmolality in a range of 250 to 350 mOsm/Kg (inclusive);
- adjusting a pH of the liquid pharmaceutical formulation with a 0.1 N solution of HCI (aq) to a pH in a range of 6.9 to 7.9 (inclusive);
- and
- adding any additional water to the liquid pharmaceutical formulation necessary to provide the Gd3+ concentration of from 70 to 700 mmol of Gd3+ ion/L to provide the liquid pharmaceutical formulation.
Dependencies are inferred from the claim text.