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Contrast medium formulation and related preparation method

An advantageous composition technology, applied in preparations for in vivo tests, medical preparations containing active ingredients, pharmaceutical formulations, etc.

Inactive Publication Date: 2015-12-09
GUERBET SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] It is undesirable for those skilled in the art to use chelating ligands free or in the form of complexes with metals or alkaline earth metals such as calcium, which have a higher Thermodynamic stability of the complex Large thermodynamic stability, as this would present a risk of exchange of the paramagnetic metal in favor of a chelate with a higher thermodynamic constant

Method used

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  • Contrast medium formulation and related preparation method
  • Contrast medium formulation and related preparation method
  • Contrast medium formulation and related preparation method

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Embodiment approach

[0059] In particular, the concentration of the above-mentioned complex of formula (I) according to the composition of the invention is between 0.001 and 1.5 mol.l -1 Between, preferably between 0.2 and 0.7mol.l -1 Between, more preferably between 0.3 and 0.6mol.l -1 between.

[0060] The complex of formula (I) is determined by methods known to those skilled in the art. In particular, it can be determined after mineralization and determination of all paramagnetic metals present in the composition. In the case of determining the total gadolinium present in solution, the determination is carried out by optical emission spectrometry (also known as ICP-AES or ICP atomic emission spectrometry).

[0061] The content of the complex of formula (I) allows the composition to have optimum contrast capability while having a satisfactory viscosity. Indeed, the above-mentioned complexes of formula (I) have less than 0.01 mol.l -1 , the level of performance as a contrast product is less ...

Embodiment 1

[0109] Embodiment 1: Embodiment according to the manufacturing method of the present invention

[0110] The method for making the composition is carried out according to the following steps:

[0111] a) 485.1 g (ie 0.5 M) of the chelating ligand of formula (I′) in the form of an odorless white powder by heating the vessel to a temperature of 50° C. and stirring the solution vigorously until the complex is completely dissolved in water with gadolinium ions (Gd 3+ ) The complex between is dissolved in water (1 liter of appropriate amount). The solution was then cooled to about 30°C.

[0112]

[0113] b) Add 1.011 g (ie relative to the ratio of the complex added in step a), 0.5% mol / mol) of DOTA (Simafex, France) to the solution obtained in step a).

[0114] c) Add 0.368 g (ie relative to the ratio of the complex compound added in step a), 0.5% mol / mol) of calcium chloride (CaCl) to the solution obtained in step b). 2 ,2H 2 O) (Merck).

[0115] c') If necessary, the pH o...

Embodiment 2

[0118] Example 2: Example of a composition according to the invention and results from studies of said composition.

[0119] By means of the method of Example 1, the following preparations are obtained:

[0120]

[0121] *Measured by colorimetry using xylenol orange

[0122] Stability under accelerated conditions and long-term stability studies

[0123] The expression "study of stability under accelerated conditions" is intended to mean a study carried out at 40°C over the course of 6 months and the expression "study of long-term stability" is intended to mean a study of 25°C over the course of 36 months Studies performed at °C (ICH conditions).

[0124] Two main entities present in the composition were measured over time.

[0125]

[0126] *Av.s = before sterilization

[0127] **Ap.s = after sterilization

[0128] ***NA = not analyzed

[0129] Free gadolinium was neither detected nor quantified in the composition. The amount of DOTA-calcium complex decreased sign...

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Abstract

The present invention relates to a liquid pharmaceutical composition including a complex of formula (I), in which M is an ion of a paramagnetic metal and R1 to R3, X1 to X3 and K1 to K12 are such as defined in claim 1, said composition also including a calcium complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. The invention also relates to the preparation method thereof and to an imaging method involving said composition.

Description

technical field [0001] The present invention relates to formulations of contrast agents, in particular paramagnetic metal ion chelates, especially for magnetic resonance imaging, and to an industrially efficient process for obtaining these formulations. Background technique [0002] A number of contrast agents based on lanthanide (paramagnetic metal) chelates, in particular gadolinium chelates, are known and described, for example, in document US Pat. No. 4,647,447. These products are usually grouped together under the term GBCA (gadolinium-based contrast agent, gadolinium-based contrast agent product). Some products are commercially available, especially based on macrocyclic chelates such as gadoterate DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N" '-tetraacetic acid), gadoteridol HPDO3A and gadobutrol DO3A-butrol, and linear chelates such as DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (gadodiamide) or BOPTA (gadoberic acid Salt). These compounds are referred to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K33/24A61K49/06A61K49/10A61K9/08A61K51/04A61K33/244
CPCA61K33/24A61K9/0009A61K9/0019A61K33/06A61K49/106A61K33/244A61K2300/00A61K49/108
Inventor C·梅迪纳M·萨巴图A·珀蒂M·波尔
Owner GUERBET SA
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