The present disclosure relates to pharmaceutical formulations of contrast agents used in magnetic resonance imaging (MRI) and methods of making and purifying the same. More specifically, disclosed are such pharmaceutical formulations of chelate complexes with lanthanide metal ions, such as gadolinium ions, as well as methods for obtaining and purifying the same. In particular, the pharmaceutical formulations are free or substantially free of water molecules coordinated with the lanthanide metal chelate complexes and provide pharmaceutical compositions that are more stable and release less lanthanide ion, specifically gadolinium ion, into the human body when injected as MRI contrast agents as compared to other typically used MRI contrast agents.
A61K 49/18 - Préparations de contraste pour la résonance magnétique nucléaire [RMN]Préparations de contraste pour l'imagerie par résonance magnétique [IRM] caractérisées par un aspect physique particulier, p. ex. émulsions, microcapsules, liposomes
C07D 257/02 - Composés hétérocycliques contenant des cycles comportant quatre atomes d'azote comme uniques hétéro-atomes du cycle non condensés avec d'autres cycles
2.
LANTHANIDE-BASED CONTRAST AGENTS HAVING IMPROVED STABILITY AND METHODS FOR THEIR PRODUCTION AND PURIFICATION
The present disclosure relates to pharmaceutical formulations of contrast agents used in magnetic resonance imaging (MRI) and methods of making and purifying the same. More specifically, disclosed are such pharmaceutical formulations of chelate complexes with lanthanide metal ions, such as gadolinium ions, as well as methods for obtaining and purifying the same. In particular, the pharmaceutical formulations are free or substantially free of water molecules coordinated with the lanthanide metal chelate complexes and provide pharmaceutical compositions that are more stable and release less lanthanide ion, specifically gadolinium ion, into the human body when injected as MRI contrast agents as compared to other typically used MRI contrast agents.
A method of preparing a stable lanthanide complex substantially free of metastable lanthanide complex and free lanthanide ion includes the steps of (i) complexing a macrocyclic chelator with a lanthanide metal in a suitable solvent to obtain a first solution of the metal complex, (ii) challenging the metal complex to cause metastable complexes to form free lanthanide ion and chelate to yield a second solution, and (iii) removing the free lanthanide ion from the second solution with a separation media.
B01D 15/36 - Adsorption sélective, p. ex. chromatographie caractérisée par le mécanisme de séparation impliquant une interaction ionique, p. ex. échange d'ions, paire d'ions, suppression d'ions ou exclusion d'ions
C07D 257/02 - Composés hétérocycliques contenant des cycles comportant quatre atomes d'azote comme uniques hétéro-atomes du cycle non condensés avec d'autres cycles
C07F 5/00 - Composés contenant des éléments des groupes 3 ou 13 du tableau périodique
B01D 15/38 - Adsorption sélective, p. ex. chromatographie caractérisée par le mécanisme de séparation impliquant une interaction spécifique non couverte par un ou plusieurs des groupes , p. ex. chromatographie d'affinité, chromatographie d'échange par ligand ou chromatographie chirale
4.
METASTABLE-FREE LANTHANIDE BASED CONTRAST AGENTS AND METHOD
A method of preparing a stable lanthanide complex substantially free of metastable lanthanide complex and free lanthanide ion includes the steps of (i) complexing a macrocyclic chelator with a lanthanide metal in a suitable solvent to obtain a first solution of the metal complex, (ii) challenging the metal complex to cause metastable complexes to form free lanthanide ion and chelate to yield a second solution, and (iii) removing the free lanthanide ion from the second solution with a separation media.
A61K 47/26 - Hydrates de carbone, p. ex. polyols ou sucres alcoolisés, sucres aminés, acides nucléiques, mono-, di- ou oligosaccharidesLeurs dérivés, p. ex. polysorbates, esters d’acide gras de sorbitan ou glycyrrhizine
A61K 47/54 - Préparations médicinales caractérisées par les ingrédients non actifs utilisés, p. ex. les supports ou les additifs inertesAgents de ciblage ou de modification chimiquement liés à l’ingrédient actif l’ingrédient non actif étant chimiquement lié à l’ingrédient actif, p. ex. conjugués polymère-médicament l’ingrédient non actif étant un agent de modification l’agent de modification étant un composé organique
B01D 15/36 - Adsorption sélective, p. ex. chromatographie caractérisée par le mécanisme de séparation impliquant une interaction ionique, p. ex. échange d'ions, paire d'ions, suppression d'ions ou exclusion d'ions
B01J 39/05 - Procédés utilisant des échangeurs organiques sous forme fortement acide
Gadolinium based contrast agents (GCA) incorporating linear ligand chelation are fundamentally different from GCAs incorporating macrocyclic ligands. The macrocyclic GCAs are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. The synthesis of linear GCAs do not form metastable complexes. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species are not regulated and quickly release free Gd3+ ions upon administration into the body. Gadolinium based contrast agents with near zero metastable species content and methods of synthesizing the same are disclosed. Gadolinium based contrast agents with long dissociation time in the body, and low free Gd3+ ion formation are obtained using a synthesis method which departs in novel ways from the traditional free Gd3+-based synthesis methods.
A61K 49/18 - Préparations de contraste pour la résonance magnétique nucléaire [RMN]Préparations de contraste pour l'imagerie par résonance magnétique [IRM] caractérisées par un aspect physique particulier, p. ex. émulsions, microcapsules, liposomes
6.
SYNTHESIS METHODS AND COMPOSITIONS OF LOW INTERMEDIATE AND LOW DICHELATE INTERMEDIATE CONTRAST AGENTS
Macrocyclic gadolinium-based contrast agents (GCA) are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species quickly release free Gd3+ ions upon delivery into the body. Aqueous or dry/solid GCA with near zero metastable species content and methods of synthesizing the same are disclosed.
A61K 49/06 - Préparations de contraste pour la résonance magnétique nucléaire [RMN]Préparations de contraste pour l'imagerie par résonance magnétique [IRM]
Macrocyclic gadolinium-based contrast agents (GCA) are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species quickly release free Gd3+ ions upon delivery into the body. Aqueous or dry/solid GCA with near zero metastable species content and methods of synthesizing the same are disclosed.
Gadolinium based contrast agents (GCA) incorporating linear ligand chelation are fundamentally different from GCAs incorporating macrocyclic ligands. The macrocyclic\GCAs are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. The synthesis of linear GCAs do not form metastable complexes. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species are not regulated and quickly release free Gd3+ ions upon administration into the body. Gadolinium based contrast agents with near zero metastable species content and methods of synthesizing the same are disclosed. Gadolinium based contrast agents with long dissociation time in the body, and low free Gd3+ ion formation are obtained using a synthesis method which departs in novel ways from the traditional free Gd3+-based synthesis methods.
A61K 49/18 - Préparations de contraste pour la résonance magnétique nucléaire [RMN]Préparations de contraste pour l'imagerie par résonance magnétique [IRM] caractérisées par un aspect physique particulier, p. ex. émulsions, microcapsules, liposomes
Gadolinium based contrast agents (GCA) incorporating linear ligand chelation are fundamentally different from GCAs incorporating macrocyclic ligands. The macrocyclicN GCAs are synthesized by pathways characterized by the formation of a sequence of metastable complexes before obtaining the final stable complex. The synthesis of linear GCAs do not form metastable complexes. Commercial macrocyclic GCAs contain unstable metastable complexes. These metastable species are not regulated and quickly release free Gd3+ ions upon administration into the body. Gadolinium based contrast agents with near zero metastable species content and methods of synthesizing the same are disclosed. Gadolinium based contrast agents with long dissociation time in the body, and low free Gd3+ ion formation are obtained using a synthesis method which departs in novel ways from the traditional free Gd3+- based synthesis methods.
Disclosed herein are complexes of gadolinium metal, ligand and meglumine that are substantially free of non-aqueous solvents. In particular, solvent-free complexes of 1) gadopentetate dimeglumine and 2) gadoterate meglumine are disclosed and methods of their preparation are disclosed. In addition, methods are disclosed for purifying reactants, monitoring and controlling pH, quantifying the free gadolinium content, quantifying the concentration of gadolinium-ligand complex in aqueous solution, and procedures for producing a drug product in one step. The one step process eliminates the need to dry the gadolinium-ligand complex, which is typically highly hygroscopic. The one step process includes purification steps that do not require the use of non-aqueous solvents.
A61K 49/18 - Préparations de contraste pour la résonance magnétique nucléaire [RMN]Préparations de contraste pour l'imagerie par résonance magnétique [IRM] caractérisées par un aspect physique particulier, p. ex. émulsions, microcapsules, liposomes
36 - Services financiers, assurances et affaires immobilières
37 - Services de construction; extraction minière; installation et réparation
Produits et services
Real estate management; real estate brokerage; real estate holding services, namely, acquisition, management, and transfer of real estate; real estate financing services; leasing of buildings and land; representation of real estate owners, namely, real estate brokerage services; financial asset management; charitable foundation services, namely, providing financial assistance for programs and service for others Real estate development; real estate construction; real estate maintenance; facilities maintenance; building facilities management; installation and maintenance of renewable resources products, namely, installation and maintenance of solar thermal installations
Disclosed herein are complexes of gadolinium metal, ligand and meglumine that are substantially free of non-aqueous solvents. In particular, solvent-free complexes of 1) gadopentetate dimeglumine and 2) gadoterate meglumine are disclosed and methods of their preparation are disclosed. In addition, methods are disclosed for purifying reactants, monitoring and controlling pH, quantifying the free gadolinium content, quantifying the concentration of gadolinium-ligand complex in aqueous solution, and procedures for producing a drug product in one step. The one step process eliminates the need to dry the gadolinium-ligand complex, which is typically highly hygroscopic. The one step process includes purification steps that do not require the use of non-aqueous solvents.
A61K 49/18 - Préparations de contraste pour la résonance magnétique nucléaire [RMN]Préparations de contraste pour l'imagerie par résonance magnétique [IRM] caractérisées par un aspect physique particulier, p. ex. émulsions, microcapsules, liposomes
A61P 13/12 - Médicaments pour le traitement des troubles du système urinaire des reins
