Claims for Patent: 12,303,573

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Summary for Patent: 12,303,573

Title:	Formulation of contrast media and process of preparation thereof
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.
Inventor(s):	Stephan Holzschuh, Thomas Frenzel, Gregor Jost, Jessica Lohrke, Wolfgang Ebert, Thomas Brumby, Wolfgang Halfbrodt
Assignee:	Bayer AG , Bayer Pharma AG
Application Number:	US18/617,245
Patent Claims:	1. 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. 2. The liquid pharmaceutical formulation of claim 1, having a concentration of a free paramagnetic metal ion M of less than or equal to 5 ppm (m/v). 3. The liquid pharmaceutical formulation of claim 1, wherein the DO3A-derived tetra-chelate has the general formula I-a 4. The liquid pharmaceutical formulation of claim 1, wherein the 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 is present in an amount sufficient to provide a pH in the range of 7.6 to 8.2; the isotonicity agent in the form of NaCl is present in an amount sufficient to provide an osmolality in a range of 200 to 400 mOsm/Kg (inclusive); the pH adjusting agent in the form of 0.1 N HCI (aq.) is 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 the pharmaceutically acceptable solvent in the form of water is 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. 5. The liquid pharmaceutical formulation of claim 4, wherein the isotonicity agent in the form of NaCl is present in an amount sufficient to provide an osmolality in a range of 250 to 300 mOsm/Kg (inclusive). 6. 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. 7. The liquid pharmaceutical formulation of claim 6, wherein the DO3A-derived tetra-chelate having the general formula I-a has a stereochemistry at its 4 chiral centers selected from RRRR, RSSS, RRSS, RRRS, and SSSS, or mixtures of any thereof. 8. The liquid pharmaceutical formulation of claim 6, wherein the liquid pharmaceutical formulation comprises: 0.075 M of the DO3A-derived tetra-chelate having the general formula I-a; 0.1% mol/mol of Ca-BT-DO3A (Calcobutrol) measured as a proportion relative to the total Gd3+ concentration in the liquid pharmaceutical formulation. 9. The liquid pharmaceutical formulation of claim 6, wherein the liquid pharmaceutical formulation comprises: about 0.10 M of the DO3A-derived tetra-chelate having the general formula I-a, providing about 400 mmol of Gd3+ ion/L; about 0.1% mol/mol of Ca-BT-DO3A (Calcobutrol) measured as a proportion relative to the total Gd3+ concentration in the liquid pharmaceutical formulation; an amount of Trometamol to be dissolved in the pharmaceutically acceptable solvent in the form of water to make about a 10 mmol/L solution of the Trometamol; an amount of sodium chloride to be dissolved in the pharmaceutically acceptable solvent in the form of water to make about a 0.05 M solution of the sodium chloride; HCI (aq) 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 an amount of water sufficient to provide a final concentration of the liquid pharmaceutical formulation having about 400 mmol of Gd3+ ion/L. 10. The liquid pharmaceutical formulation of claim 9, wherein the liquid pharmaceutical formulation comprises: about 2579 mg of the DO3A-derived tetra-chelate having the general formula I-a; about 1.960 mg of Ca-BT-DO3A (Calcobutrol); about 12.10 mg of Trometamol; about 31.4 mg of sodium chloride; the HCI (aq) in the amount sufficient to adjust the pH of the liquid pharmaceutical formulation to the pH in a range of 6.9 to 7.9; and about 8640 mg of water to provide a final volume of about 10 mL of the liquid pharmaceutical formulation. 11. 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. 12. The method of claims 11, further comprising sterilizing the liquid pharmaceutical formulation by heating the liquid pharmaceutical formulation to 121° C. for at least 15 minutes. 13. The method of claim 3, wherein the DO3A-derived tetra-chelate having the general formula I-a has a stereochemistry at its 4 chiral centers selected from RRRR, RSSS, RRSS, RRRS, and SSSS, or mixtures of any thereof. 14. The method of claim 11, wherein the DO3A-derived tetra-chelate having the general formula I-a has a stereochemistry at its 4 chiral centers selected from RRRR, RSSS, RRSS, RRRS, and SSSS, or mixtures of any thereof.