Formulation of contrast media and process of preparation thereof

Patent metadata

Field	Value
Publication number	US-11944690-B2
Application number	US-201917295647-A
Country	US
Kind code	B2
Filing date	Nov 21, 2019
Priority date	Nov 23, 2018
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

Abstract

The present disclosure relates to a liquid pharmaceutical formulation comprising a DOSA-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

The invention claimed is:

1. A liquid pharmaceutical formulation comprising a DO3A -derived tetra-chelate of general formula (I):

wherein
R 1 represents a group selected from:

wherein group * indicates the point of attachment of the group with the rest of the molecule,
R 2 , R 3 , and R 4 independently of each other represents a hydrogen atom or a group selected from: C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, (C 1 -C 2 -alkoxy)-(C 2 -C 3 -alkyl)-, and phenyl,
wherein the C 1 -C 6 -alkyl group is optionally substituted, identically or differently, with a phenyl substituent, wherein the phenyl substituent is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy, and
wherein the phenyl group is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy,

R 5 represents a group selected from:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, (C 1 -C 2 -alkoxy)-(C 2 -C 3 -alkyl)- and phenyl,
wherein the C 1 -C 6 -alkyl group is optionally substituted, identically or differently, with a phenyl substituent, wherein the phenyl substituent is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy, and
wherein the phenyl group is optionally substituted, one, two, or three times, identically or differently, with a group selected from a halogen atom, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy,

X represents a group C(═O)OH or C(═O)O−, and
M represents Gd 3+ ,
or a stereoisomer, a tautomer or a salt thereof, or a mixture of same,
wherein the formulation further comprises a pharmaceutically acceptable solvent; and
at least one compound capable of forming a chelate with a free paramagnetic metal ion M, wherein the at least one compound is Ca-BT-DO3A (Calcobutrol) in a concentration range of 0.002% to 5% mol/mol (inclusive), measured as a proportion relative to a total concentration of the Gd 3− ion in the formulation,
wherein the DO3A-derived tetra-chelate has a concentration in the formulation in a range of 60 to 750 mmol paramagnetic Gd 3− /L (inclusive).

2. The formulation according to claim 1 , wherein
R 2 represents a hydrogen atom or a methyl group,
R 3 and R 4 each represent a hydrogen atom, and
R 5 represents a group selected from methyl, ethyl, isopropyl, 2-methylpropyl, benzyl, cyclopropyl, cyclopentyl, cyclohexyl, 2-methoxyethyl, 2-ethoxyethyl, and phenyl.

3. The formulation according to claim 1 , wherein the DO3A -derived tetra-chelate of formula (I) has a structure selected from a chelate of formulae (I-a), (I-b), and (I-c):

or a stereoisomer, a tautomer or a salt thereof, or a mixture of same.

4. The formulation according to claim 3 , wherein the DO3A -derived tetra-chelate of formula (I) has the formula (I-a):

or a stereoisomer, a tautomer or a salt thereof, or a mixture of same.

5. The formulation according to claim 4 , wherein the DO3A -derived tetra-chelate of formula (I-a) has a stereochemistry at the chiral carbon of the four methyl substituents selected from the group consisting of RRRR, SSSS, RSSS, RRSS, and RRRS stereoisomers, and racemic and diastereomeric mixtures of any thereof.

6. The formulation according to claim 1 , wherein the formulation has a concentration of a free paramagnetic Gd 3+ of less than or equal to 5 ppm (m/v).

7. The formulation according to claim 1 , wherein the formulation has a pH in a range of 4.5 to 8.5 (inclusive).

8. The formulation according to claim 1 , further comprising a buffer, wherein the buffer is selected from the group consisting of a citrate buffer, a lactate buffer, an acetate buffer, a tartrate buffer, a malate buffer, a maleate buffer, a phosphate buffer, a succinate buffer, an ascorbate buffer, a carbonate buffer, a trometamol (TRIS, 2-amino-2-(hydroxymethyl)propane-1,3-diol) buffer, an HEPES (2-[4-(2-hydroxyethyl)-1-piperazine] ethanesulfonic acid) buffer, an MES (2-morpholinoethanesulfonic acid) buffer, and mixtures thereof.

9. A process for preparing a liquid pharmaceutical formulation, the process comprising the following steps:
providing a pharmaceutically acceptable solvent;
dissolving a DO3A-derived tetra-chelate of formula (I):

wherein
R 1 represents a group selected from:

wherein group * indicates the point of attachment of the group with the rest of the molecule,
R 2 , R 3 , and R 4 independently of each other represents a hydrogen atom or a group selected from: C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, (C 1 -C 2 -alkoxy)-(C 2 -C 3 -alkyl)-, and phenyl,
wherein the C 1 -C 6 -alkyl group is optionally substituted, identically or differently, with a phenyl substituent, wherein the phenyl substituent is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy, and
wherein the phenyl group is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy,

R 5 represents a group selected from:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, (C 1 -C 2 -alkoxy)-(C 2 -C 3 -alkyl)- and phenyl,
wherein the C 1 -C 6 -alkyl group is optionally substituted, identically or differently, with a phenyl substituent, wherein the phenyl substituent is optionally substituted, one, two or three times, identically or differently, with a group selected from a halogen atom, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy, and
wherein the phenyl group is optionally substituted, one, two, or three times, identically or differently, with a group selected from a halogen atom, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy,

X represents a group C(═O)OH or C(═O) O 31 , and
M represents Gd 3+ ;
or a stereoisomer, a tautomer or a salt thereof, or a mixture of same, in the pharmaceutically acceptable solvent in in sufficient amount to produce a solution of the formulation having a concentration of DO3A-derived tetra-chelate of formula (I) in a range of 60 to 750 mmol paramagnetic Gd 3− ion/L (inclusive), and
dissolving at least one compound capable of forming a chelate with Gd 3+ in sufficient amount to produce a solution having a concentration in a range of 0.002% to 5% mol/mol (inclusive) with reference to the total concentration of the Gd 3+ ion , wherein the compound capable of forming a chelate with Gd 3 + is Ca-BT-DO3A (Calcobutrol).

10. The process according to claim 9 , further comprising one or more additional steps selected from th

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