Formulation of contrast media and process of preparation thereof

Patent metadata

Field	Value
Publication number	US-12303573-B2
Application number	US-202418617245-A
Country	US
Kind code	B2
Filing date	Mar 26, 2024
Priority date	Nov 23, 2018
Publication date	May 20, 2025
Grant date	May 20, 2025

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 Gd 3+ ion, and R 1 , R 2 , R 3 , R 4 and R 5 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.

First claim

We claim:

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 Gd 3+ ion/L;
a compound capable of forming a chelate with a free gadolinium metal ion Gd 3+ comprising Ca-BT-DO3A (Calcobutrol) in a range of 0.002% to 5% mol/mol (inclusive) measured as a proportion relative to a total Gd 3+ 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 Gd 3+ 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 Gd 3+ ion/L;
a compound capable of forming a chelate with a free gadolinium metal ion Gd 3+ comprising Ca-BT-DO3A (Calcobutrol) in a range of 0.002% to 5% mol/mol (inclusive) measured as a proportion relative to a total Gd 3+ 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 Gd 3+ 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 Gd 3+ 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 Gd 3+ ion/L;
about 0.1% mol/mol of Ca-BT-DO3A (Calcobutrol) measured as a proportion relative to the total Gd 3+ 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 Gd 3+ 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 Gd 3+ 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 Gd 3+ concentration of from 70 to 700 mmol of Gd 3+ ion/L to provide the liquid pharmaceutical formulation.

12. The method of claims 11 , further comprising sterilizing the liquid pharmaceutical formulation by heating the liqu

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Holzschuh Stephan
• Frenzel Thomas
• Jost Gregor
• Lohrke Jessica
• Ebert Wolfgang
• Brumby Thomas
• Halfbrodt Wolfgang

Classifications

• A61K49/106

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• A61K49/108 Primary

  the metal complex being Gd-DOTA · CPC title

• A61K49/18

  characterised by a special physical form, e.g. emulsions, microcapsules, liposomes · CPC title

• A61K49/124 Primary

  dendrimers, dendrons, hyperbranched compounds · CPC title

• A61K49/085

  conjugated systems · CPC title