Process for producing a complex of a lanthanide with a macrocyclic ligand
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A technology of macrocyclic ligands and lanthanides, which can be used in pharmaceutical formulations, drug delivery, preparations for in vivo tests, etc.
Inactive Publication Date: 2015-11-18
T2PHARMA GMBH
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This increases the complexity of the production process and increases the risk of error and the introduction of microbial contamination
Moreover, it also makes the method more expensive and time-consuming
Furthermore, adjustment of the ligand or lanthanide concentration in the final drug formulation using ligand solutions cannot be achieved with great precision, as ligands in powder form absorb water very quickly, which can cause significant weighing errors
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[0073] Measurement
[0074] Moisture content in DOTA
[0075] The measurement of the moisture content in DOTA was performed as described in Karl Fischer's semi-micro method (Fischer, Karl - Pharm. Eur. Section 2.5.12).
[0076] Analysis of free form of DOTA in solution (free DOTA)
[0077] Solution A: Dissolve 50 g of sodium acetate in 10 ml of glacial acetic acid and adjust the volume to 1000.0 ml with carbon dioxide-free water. The obtained solution was adjusted to pH (5±0.05) with 0.1 M sodium hydroxide solution or glacial acetic acid.
[0078] Solution B: Dissolve 50.8 mg of xylenol orange in carbon dioxide-free water and adjust the volume to 100.0 ml with the same solvent. Use freshly prepared solutions.
[0079] Solution C: 3 mL of Solution B was added to 30 mL of Solution A, and the volume of this solution was increased to 200.0 mL with carbon dioxide-free water.
[0080] A 0.005M solution of gadolinium sulfate was prepared as follows: 3.735 grams of gadolinium sul...
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Abstract
The present invention relates to a process for preparing a macrocyclic ligand and for producing a pharmaceutical liquid formulation comprising a complex of said ligand with a lanthanide or similar compounds. The macrocyclic ligand of the present invention is a derivative of tetraaza macrocycles such as 1,4,7,10-tetraazacyclododecane (cyclen), 1,4,7,10-tetrazacyclotridecan (homocyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam), such as DOTA, TRITA, TETA, DOTMA, TCE-DOTA, DOTA-pNB, D03A, HP-D03A, D03A-butrol, D03MA, ODOTRA, D03A-L2, DOTP, DOTMP, DO2a, THP, THED, DOTAM, DOTTA. The preferred lanthanide and similar compounds are Gadolinium (Gd), Yttrium (Y) and Terbium (Tb). The process of the present invention aims to obtain an accurate balance between the ligand and the lanthanide, and to avoid the presence of free lanthanide in said formulation, by calculating the necessary amount of ligand for a formulation batch, measuring the moisture content of a sample of the material in said batch, calculating the total amount of moisture present of the batch and calculating the total amount of material which is required to prepare the batch size. In this way, the production of a pharmaceutical liquid formulation comprising a complex of a macrocyclic ligand with lanthanide is more accurate, faster and easier. The present invention is thus useful for the production of pharmaceutical liquid formulations comprising a complex of a macrocyclic ligand with a lanthanide, which can be used as contrast agents for magnetic resonance imaging.
Description
technical field [0001] The present invention relates to a process for the manufacture of complexes of lanthanide or similar compounds with ligands which can be used as contrast agents for magnetic resonance imaging. Background of the invention [0002] Magnetic resonance imaging (MRI) is a powerful non-invasive technique for producing detailed two- or three-dimensional anatomical images of tissues in the body. Conventional MRI using protons 1 As its signal source, H is very abundant in tissues and it has the highest sensitivity of all biologically relevant nuclei. [0003] The contrast that can produce differences in internal structures in an image comes from how the signal attenuates and is the difference between the signals from two tissue regions. The route by which the protons release the energy they absorbed from the RF pulse and thereby reduce the transverse magnetization and cause signal attenuation is called relaxation. In MRI, two independent relaxation processes...
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