Formulation of contrast media and process of preparation thereof
Inventors
HOLZSCHUH, STEPHAN • Frenzel, Thomas • Jost, Gregor • Lohrke, Jessica • Ebert, Wolfgang • Brumby, Thomas • Halfbrodt, Wolfgang
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12303573-B2
Publication Date
2025-05-20
Expiration Date
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.
Core Innovation
The invention relates to a liquid pharmaceutical formulation comprising a DO3A-derived tetra-chelate having a general formula selected from 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. The formulation further includes Ca-BT-DO3A (Calcobutrol), a compound capable of forming a chelate with a free gadolinium metal ion Gd3+, in a range of 0.002% to 5% mol/mol relative to total Gd3+ concentration.
The formulation further comprises 10.0 mmol/L Trometamol (TRIS, 2-amino-2-(hydroxymethyl)propane-1,3-diol), NaCl as an isotonicity agent, HCl (aq.) as a pH adjusting agent, and water as a pharmaceutically acceptable solvent. The disclosed formulations impose quantitative constraints on pH and osmolality, including buffer pH in the range of 7.6 to 8.2, adjusted pH in the range of 6.9 to 7.9, and osmolality in the range of 250 to 350 mOsm/Kg.
The invention also defines related tetra-chelate stereochemical selections, including stereochemistry at the four chiral centers of the DO3A-derived tetra-chelate selected from RRRR, RSSS, RRSS, RRRS, SSSS, or mixtures thereof. The disclosed approaches also address preparing such liquid pharmaceutical formulations by providing water, buffering with Trometamol (TRIS), forming chelate compositions with Ca-BT-DO3A (Calcobutrol), dissolving the DO3A-derived tetra-chelate to achieve the Gd3+ concentration range, adjusting isotonicity using NaCl to achieve a specified osmolality, and adjusting pH with HCl (aq.).
Claims Coverage
The consolidated material covers three independent claims: a liquid pharmaceutical formulation with DO3A-derived tetra-chelates of formulae (I-a), (I-b), and (I-c); a narrower liquid pharmaceutical formulation with general formula I-a; and a method for making the liquid pharmaceutical formulation. Across these claims, the inventive features center on defined DO3A-derived tetra-chelate content, Ca-BT-DO3A (Calcobutrol) as a chelate-forming compound for free gadolinium metal ion Gd3+, and defined buffer, isotonicity, pH, water, and Gd3+ concentration conditions.
DO3A-derived tetra-chelate formulation with defined Gd3+ range
A liquid pharmaceutical formulation comprising a DO3A-derived tetra-chelate having a general formula selected from 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.
Ca-BT-DO3A (Calcobutrol) for chelating free gadolinium metal ion
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 relative to total Gd3+ concentration in the liquid pharmaceutical formulation.
Trometamol (TRIS) buffer, NaCl isotonicity, and HCl pH adjustment with water solvent
A buffer in the form of 10.0 mmol/L Trometamol (TRIS), an isotonicity agent in the form of NaCl, a pH adjusting agent in the form of HCl (aq.), and a pharmaceutically acceptable solvent in the form of water.
Liquid pharmaceutical formulation constrained to specific pH and osmolality ranges
A liquid pharmaceutical formulation comprising a DO3A-derived tetra-chelate having 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; Ca-BT-DO3A (Calcobutrol) in a range of 0.002% to 5% mol/mol relative to total Gd3+ concentration; 10.0 mmol/L Trometamol (TRIS) with pH in the range of 7.6 to 8.2; NaCl providing an osmolality in the range of 250 to 350 mOsm/Kg; HCl (aq.) adjusting pH to 6.9 to 7.9; and water sufficient to provide the range of 70 to 700 mmol of Gd3+ ion/L.
Method for making the liquid pharmaceutical formulation with defined buffer, Ca-BT-DO3A, NaCl osmolality, and pH
A method for making a liquid pharmaceutical formulation comprising water; Trometamol buffer; Ca-BT-DO3A (Calcobutrol); a DO3A-derived tetra-chelate having general formula I-a; sodium chloride as isotonicity agent; and pH adjustment with HCl (aq.), under defined pH, osmolality, and Gd3+ concentration ranges.
Across the independent claims, the inventive coverage focuses on a liquid pharmaceutical formulation containing a DO3A-derived tetra-chelate in a defined Gd3+ concentration range, combined with Ca-BT-DO3A (Calcobutrol) at a defined mol/mol proportion relative to total Gd3+ to chelate free gadolinium, and formulated with defined buffer, pH adjustment, and NaCl isotonicity conditions. The method claim covers preparing the formulation by combining the specified components in water and adjusting pH and osmolality to the stated ranges while achieving the target Gd3+ concentration range.
Stated Advantages
Maintains free paramagnetic metal ion concentration essentially zero with limits of ≤42 ppm (m/v) over ≥56 months at 25°C and 40°C.
Provides defined metal scavenging capacity for DO3A-derived tetra-chelate metal-scavenging complexes.
Reduced free metal exposure, including reduced free metal ppm.
High relaxivity.
Favorable pharmacokinetics.
High stability/solubility.
Potential dose reduction and whole-body imaging.
Improved tolerability.
Viscosity.
Isotonicity with blood plasma.
Documented Applications
Use as a liquid pharmaceutical formulation containing Gd3+ in the stated concentration and formulation condition ranges.
Magnetic Resonance Imaging (MRI) whole-body/region imaging using the liquid pharmaceutical formulation as an intravenous dose form.
MRI contrast.
Liquid pharmaceutical contrast medium for MRI for whole-body or regional imaging.
Interested in licensing this patent?