Novel method for producing gadolinium complex

A technology of complexation and chelation, which is applied in the field of preparation of Gd-DOTA magnetic resonance imaging contrast agent, which can solve the problems of gadolinium ion toxicity and so on

Pending Publication Date: 2022-08-02
GE HEALTHCARE AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, free gadolinium ions may exhibit significant toxicity in vivo

Method used

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  • Novel method for producing gadolinium complex
  • Novel method for producing gadolinium complex
  • Novel method for producing gadolinium complex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1 is a comparative example describing a known method for removing free Gd ions from meglumine Gd-DOTA solutions.

Embodiment 2

[0086] Example 2 is a method of the present invention for removing free Gd ions from meglumine Gd-DOTA solutions.

[0087] List of Abbreviations Used in Examples

[0088] CAD with Electrosol Detector

[0089] DAD Diode Array Detector

[0090] DIW deionized water

[0091] HPLC High Performance Liquid Chromatography

[0092] MeCN Acetonitrile

[0093] OAc acetate

[0094] RT room temperature

[0095] TOF flight time

[0096] UPLC Ultra Performance Liquid Chromatography.

Embodiment 3

[0121] Example 3: Industrial production of Gd-DOTA meglumine using the method of the present invention.

[0122] Dissolve DOTA (370 kg (range: 310-410 kg)) in boiling water (2000 kg) and add Gd 2 O 3 (162.8 kg (range: 135-190 kg)). The temperature was set up to 80°C and stirred overnight. The presence of free gadolinium ions was determined by colorimetric titration.

[0123] The temperature was adjusted to 50°C and meglumine was added to achieve pH 5.7 (range: 5.5-6.4). 160 kg (range: 150-200 kg) meglumine were initially added and final pH adjustment was performed with an aqueous solution of meglumine (1.5M).

[0124] The temperature of the Gd-DOTA meglumine solution was further adjusted to 40°C. Place 4 MCN activated carbon modules in series. The first 3 filter chambers contained 1.01 kg of activated carbon, while the last contained 2.7 kg of activated carbon. MCN activated carbon was pretreated before pumping Gd-DOTA meglumine solution. The MCN activated carbon w...

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Abstract

The present invention provides a novel method of removing gadolinium ions from a solution comprising gadolinium complexed with DOTA. The method of the present invention is relatively simple and cost effective compared to known methods.

Description

technical field [0001] The present invention generally relates to a method for removing gadolinium ions from complexes of gadolinium and DOTA. The method uses activated carbon to remove excess gadolinium ions. Also provided are methods of making Gd-DOTA magnetic resonance imaging (MRI) contrast agents comprising the gadolinium removal methods of the present invention. Background technique [0002] Metal complexes of lanthanide metals, especially gadolinium, are of interest as MRI contrast agents in the field of in vivo medical imaging. MRI contrast agents based on gadolinium metal complexes have been extensively reviewed [see, for example, Zhang et al., Curr.Med.Chem., 12 , 751-778 (2005) and Aime et al., Adv.Inorg.Chem., 57 , 173-237 (2005)]. [0003] However, free gadolinium ions may exhibit significant toxicity in vivo. US 5,876,695 addresses this problem by including an additive in the formulation of the gadolinium metal complex, such as a "weak metal chelate comple...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/02A61K49/10A61K49/18
CPCC07D257/02A61K49/18A61K49/108C07F5/00A61K49/10A61K2123/00
Inventor M·萨宁A·梅耶
Owner GE HEALTHCARE AS
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