DE102015013939A1 - Process for the preparation of gadoteric acid (Gd-DOTA) complexes - Google Patents

Abstract

The present invention relates to a process for the preparation of a liquid parenteral formulation of gadoteric meglumine for use as a contrast agent for magnetic resonance imaging.

Description

BACKGROUND OF THE INVENTION

Gadoteric acid (Gd-DOTA) is an active substance approved as a contrast agent for magnetic resonance imaging. The chemical name for gadoteric acid is gadolinium (+3); 2- [4,7,10-tris (carboxymethyl) -1,4,7,10-tetrazacyclododec-1-yl] acetic acid. The connection has the following structure:

Gadoteric acid in the form of its meglumine salt ( "gadoteric meglumine") is marketed by Guerbet under the trade name DOTAREM ^®.

Each molecule of gadoteric acid contains a gadolinium ion complexed by a molecule of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Compared to similar gadolinium complexes such as gadopentetic acid, gadobenic acid, gadoxetic acid, gadoteridol or gadobutrol, gadoteric acid is the most stable gadolinium complex.

A synthesis of DOTA is described in the WO 2013/076743 disclosed.

The use of gadoterate as a contrast agent in EP 0 270 483 B1 described.

Free ions of gadolinium, ie non-complexed gadolinium, are very toxic. Among several related compounds used to complex gadolinium, DOTA forms the thermodynamically and kinetically most stable complexes with gadolinium. However, the very stable complexes of Gd-DOTA also tend to release gadolinium. To prevent the undesirable release of gadolinium, DOTA is usually added in excess. But since free DOTA itself is toxic, the surplus must be kept within a certain range.

The prior art reports that it is not possible to obtain solutions of gadoteric meglumine for injection with an excess of DOTA in the desired target range by simply weighing and mixing gadolinium oxide, DOTA and meglumine in water.

To overcome this obstacle, the beats WO 2009/103744 after mixing the initial amounts of gadolinia and DOTA, measuring the concentration of free gadolinium oxide in the liquid drug formulation and then adding the free DOTA to obtain an excess of free ligand in the desired concentration range.

WO 2014/161925 describes a process for preparing a complex of a lanthanide or similar compound with a macrocyclic ligand based on the measurement of the material containing the macrocyclic ligand.

In order to achieve a final pharmaceutical composition with a DOTA concentration within the specifications, both conventional methods described above require additional steps such as the measurement of free gadolinium and the moisture content in the DOTA.

It is therefore desirable to obtain a simpler process for the preparation of liquid formulations of gadoteric meglumine for pharmaceutical use which is also suitable for industrial scale application.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of a liquid parenteral pharmaceutical formulation containing gadoteric meglumine.

• a) Mischen einer vorbestimmten Menge von Gadoliniumoxid, DOTA und Meglumin in Wasser.
• b) Einstellung des pH-Wertes des Gemisches einen pH-Wert zwischen 6,5 und 8,0 durch Zugabe von DOTA oder jede geeignete Säure,

wobei die Menge an freiem DOTA im Bereich von 0,002% bis 0,5% liegt und der Gehalt an freiem Gadolinium weniger als 0,02% beträgt.The invention further relates to a process for the preparation of a liquid pharmaceutical formulation of gadoteric meglumine, comprising the following steps:

• a) Mixing a predetermined amount of gadolinium oxide, DOTA and meglumine in water.
• b) adjusting the pH of the mixture to a pH between 6.5 and 8.0 by adding DOTA or any suitable acid,

wherein the amount of free DOTA is in the range of 0.002% to 0.5% and the content of free gadolinium is less than 0.02%.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have found that an accurate level of free DOTA in the final dosage form can be readily obtained by titrating a solution of gadoteric meglumine with DOTA or an acid until a desired pH is achieved. This method is simpler than the time-consuming process measurement of gadolinium and / or free DOTA as described in the prior art.

In the context of the present invention, the term "free DOTA" means any DOTA which is not complexed with gadolinium or other metal ions.

In the context of the present invention, the term "free gadolinium" means any gadolinium which is not chelated with DOTA.

In the context of the present invention, the term "gadolinic meglumine" comprises complexes of gadolinium oxide (Gd ₂ O ₃ ) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) in the form of the Meglumine salt, ie DOTA-Gd-meglumine.

Furthermore, in the context of the present invention, all amounts stated in percent ("%") relate to amounts mol / mol.

• a) Mischen einer vorbestimmten Menge von Gadoliniumoxid, DOTA und Meglumin in Wasser.
• b) Einstellen des pH-Wertes des Gemisches durch Zugabe von DOTA oder eine geeignete Säure auf einen pH-Wert zwischen pH 6,5 und pH 8,0;

wobei die Menge des freien DOTA im Bereich von 0,002% bis 0,5% und der Gehalt an freiem Gadolinium 0,02% oder weniger beträgt.According to the present invention, the process for preparing a liquid pharmaceutical formulation of gadoteric meglumine comprises the steps of:

• a) Mixing a predetermined amount of gadolinium oxide, DOTA and meglumine in water.
• b) adjusting the pH of the mixture by adding DOTA or a suitable acid to a pH between pH 6.5 and pH 8.0;

wherein the amount of free DOTA is in the range of 0.002% to 0.5% and the content of free gadolinium is 0.02% or less.

Thus, in an advantageous embodiment, the amounts of free DOTA and Gd ₂ O ₃ are added so that either not all DOTA is complexed with the Gd ₂ O ₃ or that not all the Gd ₂ O _{3 is} complexed with DOTA. Thus, after step b), the pharmaceutical formulation typically contains the DOTA-gadolinium complex and either free DOTA or free gadolinium.

Advantageously, the pharmaceutical formulation according to the present invention is characterized in that the formulation contains about 0.002 to 0.5% free DOTA and 0.02% or less free gadolinium.

Formulations according to the present invention have a pH of about 6.5 to 8.0. The desired pH of the formulation is treated with DOTA or any suitable acid such as e.g. As mineral acids, organic carboxylic acids, sulfonic acids and the like. Suitable acids include Hydrochloric, sulfuric, boric, silicic, acetic, phosphoric, formic, maleic, citric, trichloroacetic, trifluoroacetic, benzoic, fumaric, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic and the like.

• i. Wasser zur Injektion wird in einem Herstellungsbehälter auf etwa 80 ± 5°C erhitzt.
• ii. DOTA wird zu der obigen Lösung zugegeben und gut gerührt.
• iii. Gadoliniumoxid (Gd₂O₃) wird zu der obigen Lösung hinzugegeben und gerührt, bis es vollständig in Lösung geht, wobei die Temperatur der Lösung bei 80 ± 5°C beträgt.
• iv. Die Lösung wird auf 25 ± 2°C abgekühlt und Meglumin wird zu der Lösung gegeben und gerührt.
• v. Optional wird der pH-Wert der Lösung auf einen Wert von 7,5 bis 8,0 unter Verwendung von Mineralsäure wie Salzsäure eingestellt.
• vi. Der endgültige pH-Wert der Lösung wird auf etwa 6,5 bis 8,0 durch die Zugabe von DOTA oder Säure eingestellt.
• vii. Die Lösung wird filtriert und in geeignete Behälter oder Fläschchen gefüllt, verschlossen und versiegelt abschließend terminal sterilisiert.

The gadoteric meglumine injection process of the present invention comprises the following steps:

• i. Water for injection is heated in a production vessel to about 80 ± 5 ° C.
• ii. DOTA is added to the above solution and stirred well.
• iii. Gadolinium oxide (Gd ₂ O ₃ ) is added to the above solution and stirred until it completely dissolves with the temperature of the solution being 80 ± 5 ° C.
• iv. The solution is cooled to 25 ± 2 ° C and meglumine is added to the solution and stirred.
• v. Optionally, the pH of the solution is adjusted to a value of 7.5 to 8.0 using mineral acid such as hydrochloric acid.
• vi. The final pH of the solution is adjusted to about 6.5 to 8.0 by the addition of DOTA or acid.
• vii. The solution is filtered and filled into suitable containers or vials, sealed and finally terminal sterilized.

The inventors have carried out experiments to optimize the process to obtain the desired, safe, product. Experiments were performed to limit the amount of free DOTA and free gadolinium and thus reduce the toxicity of the product. Formulations prepared according to the invention were tested for various parameters such as pH, assay, free gadolinium content and free DOTA content. The results are summarized in Table 1. The amount of gadolinium free in the formulation was determined by means of an Agilent fluorescence detector. The amount of free DOTA present in the formulation is determined by HPLC method. Example / Table 1: pH adjustment with DOTA F1 F2 parameter start value After pH adjustment start value After pH adjustment pH of the solution 8.10 7.40 7.70 7.32 assay 99.9% 99.7% 99.8% 99.7% Content of free Gd 0.107% Not detected Not detected Not detected Content of free DOTA Not detected 0.057% 0.193% 0.292%

From the above results, it can be concluded that the manufacturing process by the pH adjustment method is more appropriate and the specifications for gadoteric meglumine injection are met.

The invention according to the formulation prepared was coated with commercially available gadoteric meglumine preparations for injection, ie, DOTAREM ^® Injection (12GD100A, 11GD089A Batch No) compared. The results are listed in Table 2: Table 2: Comparison with DOTAREM ^® parameter DOTAREM (12GD100A) DOTAREM (11GD089A) Inventive product (F-1) pH of the solution 7.10 7.20 7.50 assay 98.1% 99.1% 98.8% Content of free Gd Not detected Not detected Not detected Content of free DOTA 0.076% 0.051% 0.040%

From Table 2 it can be seen that the product produced according to the invention is comparable to the commercially available product.

The following examples describe certain aspects and embodiments of the present invention and demonstrate their practical advantages. The examples are illustrative only and are not intended to limit the scope of the invention in any way. example 1 S. No ingredient Quantity per ml 1 DOTA 0.20246 g 2 Gadolinium oxide (Gd ₂ O ₃ ) 0.09062 g 3 meglumine 0.0976 g 4 Dil. HCl qs 5 Water for injections qs to 1 mL

Manufacturing process

Water for injections was heated to 80 ± 5 ° C in a manufacturing container. DOTA was added and stirred followed by the addition of gadolinium oxide while maintaining the temperature at 80 ± 5 ° C. The solution was cooled to 25 ± 2 ° C, then meglumine added and stirred until a homogeneous solution was obtained. The pH of the solution was adjusted to about 7.5 to 8.0 with hydrochloric acid. The final pH of the solution was adjusted to about 7.3 ± 0.2 using DOTA. The resulting solution was filtered and then filled into ampoules. Example 2 S. No ingredient Quantity per ml 1 DOTA 0.21246 g 2 Gadolinium oxide (Gd ₂ O ₃ ) 0.09062 g 3 meglumine 0.0976 g 4 Water for injections qs to 1 mL

Manufacturing process

Water for injections was heated to 80 ± 5 ° C in a manufacturing container. DOTA was added and stirred followed by the addition of gadolinium oxide while maintaining the temperature at 80 ± 5 ° C. The solution was cooled to 25 ± 2 ° C, then meglumine added and stirred until a homogeneous solution was obtained. The pH of the solution was adjusted to about 7.3 ± 0.2 with DOTA. The resulting solution was filtered and then filled into ampoules. Example 3 S. No ingredient Quantity per ml F1 F2 1 DOTA 0.21307 g 0.21307 g 2 Gadolinium oxide (Gd ₂ O ₃ ) 0.09089 g 0.0910 g 3 meglumine 0.0976 g 0.0976 g 4 Water for injections qs to 1 mL qs to 1 mL

Manufacturing process

Water for injections was heated to 80 ± 5 ° C in a manufacturing container. DOTA was added and stirred followed by the addition of gadolinium oxide while maintaining the temperature at 80 ± 5 ° C. The solution was cooled to 25 ± 2 ° C, then meglumine added and stirred until a homogeneous solution was obtained. The pH of the solution was adjusted to about 7.3 ± 0.2 with DOTA. The resulting solution was filtered and then filled into ampoules. Example 4 S. No ingredient Quantity per ml 1 DOTA 0.20246 g 2 Gadolinium oxide (Gd ₂ O ₃ ) 0.09062 g 3 meglumine 0.0976 g 4 acetic acid qs 5 Water for injections qs to 1 mL

Manufacturing process

Water for injections was heated to 80 ± 5 ° C in a manufacturing container. DOTA was added and stirred followed by the addition of gadolinium oxide while maintaining the temperature at 80 ± 5 ° C. The solution was cooled to 25 ± 2 ° C, then meglumine added and stirred until a homogeneous solution was obtained. The pH of the solution was adjusted to about 7.4 with acetic acid. The resulting solution was filtered and then filled into ampoules. Example 5 S. No ingredient Quantity per ml 1 DOTA 0.20246 g 2 Gadolinium oxide (Gd ₂ O ₃ ) 0.09062 g 3 meglumine 0.0976 g 4 phosphoric acid qs 5 Water for injections qs to 1 mL

Manufacturing process

Water for injections was heated to 80 ± 5 ° C in a manufacturing container. DOTA was added and stirred followed by the addition of gadolinium oxide while maintaining the temperature at 80 ± 5 ° C. The solution was cooled to 25 ± 2 ° C, then meglumine added and stirred until a homogeneous solution was obtained. The pH of the solution was adjusted to about 7.4 with phosphoric acid and / or DOTA. The resulting solution was filtered and then filled into ampoules.

• a) Mischen einer vorbestimmten Menge von Gadoliniumoxid und DOTA und Meglumin in Wasser
• b) Einstellen des pH-Wertes des Gemisches auf einen pH-Wert zwischen pH 6,50 und pH 8,00, bevorzugt auf einen pH-Wert zwischen pH 7,0 und pH 7,80, durch Zugabe von DOTA oder eine andere Säure

The present invention further provides a liquid pharmaceutical composition containing gadoterate meglumine, wherein the ratio of DOTA in free form with respect to gadoteric acid ranges from 0.002% to 0.5% mol / mol and the content of gadolinium with respect to gadoteric acid 0.02% or less, prepared by a process comprising the following steps:

• a) Mixing a predetermined amount of gadolinium oxide and DOTA and meglumine in water
• b) adjusting the pH of the mixture to a pH between pH 6.50 and pH 8.00, preferably to a pH between pH 7.0 and pH 7.80, by adding DOTA or another acid

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2013/076743 [0004]
• EP 0270483 B1 [0005]
• WO 2009/103744 [0008]
• WO 2014/161925 [0009]

Claims (3)

A process for the preparation of a liquid pharmaceutical formulation containing gadoteric meglumine comprising the steps of: a) Mixing a predetermined amount of gadolinium oxide and DOTA and meglumine in water b) adjusting the pH of the mixture to a pH between pH 6.5 and pH 8.0 by adding DOTA or another acid A process for producing a liquid pharmaceutical containing gadoteric meglumine according to claim 1, wherein the amount of free DOTA in the formulation is in the range of about 0.002% to 0.5% and the content of free gadolinium is 0.02% or less. A process for the preparation of the formulation of claim 1, wherein the pH of the formulation is adjusted to a value in the range of 7.0 to 7.8.