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Process for preparing a pharmaceutical formulation of contrast agents

A preparation and drug technology, applied in the field of chelate complexes and nuclear magnetic resonance imaging, can solve the needs of perfect control rate, complex tolerance problems and other problems

Active Publication Date: 2012-08-29
GUERBET SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In conclusion, the problem of tolerability of said complexes of chelates with lanthanides remains complex and important, leading to research on more safe products and to the need for perfectly controlled ratios of the different entities in pharmaceutical solutions

Method used

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  • Process for preparing a pharmaceutical formulation of contrast agents
  • Process for preparing a pharmaceutical formulation of contrast agents
  • Process for preparing a pharmaceutical formulation of contrast agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] 1) Example 1: Tolerance in vivo

[0190] Tolerability results in Table 2 (acute toxicity in mice for DOTA diagnostic solution; this solution is an injected drug solution and contains DOTA with Gd 3+ complexes and not composed of Gd 3+ Excess free DOTA complexed and not complexed by metal ions as excipients) showed that formulations containing free macrocyclic chelate DOTA from 0.025 mol / mol% to 0.25 mol / mol% were three times less toxic at close to 2% of the formulation.

[0191]

[0192]

[0193] Additional stability studies carried out by the applicant showed that the formulations were very satisfactorily free of gadolinium release over long storage times.

Embodiment 2

[0194] Example 2: Process for the preparation of formulations of lanthanide chelates (mixture of chelate solution and lanthanide solution)

[0195] The preparation of formulations in which the macrocyclic chelate is DOTA is more precisely described. Table 3 below gives an example of the quantities (industrial quantities) used for the manufacture of 100 liters of DOTA solution.

[0196]

[0197] (1) 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid

[0198] step 1 : dissolve

[0199] 40 liters of injection grade water was placed in a 100-liter manufacturing tank at 80°C, nitrogen injection was started, and then 20.100 kg of DOTA and 9.135 kg of gadolinia were mixed under agitation. Complexation is performed at a pH below 6, for example between 3 and 6, for example at pH 4. Gadolinium oxide forms a water-soluble acidic complex in the presence of DOTA.

[0200] step 2 :Measurement

[0201] After step 1, samples were taken and free gadolinium was determined...

Embodiment 3

[0214] 2) Example 3: Process for making formulations of lanthanide chelates (Dissolution of solid complexes [chelates-lanthanides])

[0215]

[0216] This example illustrates the manufacture of a small number of products, with appropriate exchange on an industrial scale.

[0217]

[0218] In a three-necked flask equipped with a condenser, a thermometer, and a pH meter, 10 g (0.025 mol; 1 equivalent) of the macrocyclic chelate DOTA was dissolved in 200 ml of water by heating to 80°C. The measured pH was 3.7. Adjust it to 6 with 2N NaOH solution. 4.48 g (0.0125 mol; 0.5 equivalents) of gadolinia were added. The pH was adjusted and kept stable between 6 and 7 by adding 1N HCl. The reaction was placed at 80 °C with stirring.

[0219] Residual free gadolinium was removed by means of a chelex resin prewashed with water. In order to do this, the reaction mixture was brought to pH 5 (resin is more effective). The whole was left at room temperature for 2 hours with stirri...

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Abstract

The invention relates to a process for preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide and a mol / mol amount offree macrocyclic chelate of between 0.002% and 0.4%, advantageously between 0.02% and 0.3% and very advantageously between 0.025% and 0.25%, the macrocyclic chelate advantageously being chosen from DOTA, NOTA, DOTAGA, DO3A, BT-DO3A, HP-DO3A and PCTA, and is preferably DOTA, the said process comprising the following successive steps: b) preparation of a liquid pharmaceutical composition containing, firstly, the complex of macrocyclic chelate with a lanthanide, and, secondly, free macrocyclic chelate and / or free lanthanide; c) measurement in the pharmaceutical formulation obtained in step b) of the concentration of free macrocyclic chelate C chl and / or of free lanthanide C lanl; d)adjustmentof C chl and / or of C lanl so as to obtain C chl = C tchl and C lanl = 0, wherein C t chl is the target concentration of free macrocyclic chelate in the final liquid pharmaceutical formulation.

Description

technical field [0001] The present invention relates to pharmaceutical formulations of contrast agents, in particular complexes of chelates with paramagnetic metal ions, especially for nuclear magnetic resonance imaging, and to industrially effective methods for obtaining these formulations Methods. Background technique [0002] A number of contrast agents based on complexes with lanthanides (paramagnetic metals), especially with chelates of gadolinium, are known and described, for example, in document US4647447. Several products are already on the market, especially based on macrocyclic chelates, such as DOTA gadoterate (1,4,7,10-tetraazacyclo-dodecane-N,N',N", N"'-tetraacetic acid) and gadoteridol HPDO3A, and linear chelates such as DTPA (diethylenetriaminepentaacetic acid) and DTPA-BMA (gadodiamide). [0003] In vivo, complexes with chelates of lanthanides are in a state of chemical equilibrium, which can lead to the risk of undesired release of lanthanides, and in part...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K49/06
CPCA61K49/108A61K49/106A61K45/06A61K31/28A61P43/00A61K9/0019A61K47/18G01N33/15
Inventor D·梅耶尔C·科罗M·波尔V·巴博坦B·博纳曼
Owner GUERBET SA
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