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Formulation of contrast media and process of preparation thereof

A preparation and group technology, which can be used in MRI/MRI contrast agents, pharmaceutical formulations, preparations for in vivo tests, etc., can solve problems such as limitations, and achieve low viscosity, increased tolerance, and good local resistance. receptive effect

Pending Publication Date: 2021-07-23
BAYER AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the toxicity of some chelated ligands may also limit the amount of free ligand that can be added to the formulation

Method used

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  • Formulation of contrast media and process of preparation thereof
  • Formulation of contrast media and process of preparation thereof
  • Formulation of contrast media and process of preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

no. 4 approach

[0113] According to a fourth embodiment of the first aspect, the present disclosure encompasses the above liquid pharmaceutical formulation, wherein the DO3A-derived tetrachelate of formula (I) has the following formula (I-a):

[0114]

[0115] Or stereoisomers, tautomers or salts thereof, or mixtures thereof.

[0116] According to a fifth embodiment of the first aspect, Gd of the above general formula (I) according to the formulation of the present disclosure 4 -DO3A-derived tetrachelates at concentrations between 60 and 750 mmol Gd 3+ / L range (inclusive), especially in the range of 70 to 700mmolGd 3+ / L range (inclusive), especially in the range of 80 to 650mmol Gd 3+ / L range (inclusive), especially 90 to 600mmol Gd 3+ / L range (inclusive), especially in the range of 100 to 500mmol Gd 3+ / L range (inclusive), especially in the range of 150 to 450mmol Gd 3+ / L range (inclusive), more particularly in the range of 200 to 400mmol Gd 3+ / L range (inclusive), even more ...

Embodiment 3

[0339] **Pediatric Adrenaline. September 13, 2018

[0340] ***Fachinformation des Arzneimittel-Kompendium der

[0341] # Prescribing Information Highlights (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2017 / 204781s001lbl.pdf)

[0342] ## J. Magn. Res. Imaging, 25, 884-899, 2007

[0343] According to the thirty-first embodiment of the first aspect, the pH of the preparation may be in the range of 4.5 to 8.5 (inclusive), especially in the range of 6.6 to 8.0 (inclusive), more particularly in the range of 6.9 to 7.9 inclusive, more particularly 7.2 to 7.6. More particularly, wherein the pH is 7.4. Formulations with a pH within these ranges in particular make it possible to have an isohydric solution compared to in vivo conditions (pH 7.4).

[0344]According to a twenty-second embodiment of the first aspect, the formulations according to various embodiments of the present disclosure may be buffered, i.e. they comprise a buffer selected from the group established f...

Embodiment 1

[0491] Example 1 - Gd comprising formula (I-a) 4 - Production of liquid pharmaceutical formulations of DO3A-derived tetrachelates and Ca-BT-DO3A (Calcobutrol)

[0492] The method for producing a liquid pharmaceutical preparation is carried out according to the following steps:

[0493] a) Fill 720.5 g of water for injection into the manufacturing container, and dissolve 1.217 g of tromethamine while stirring. The pH of the solution obtained in step a) was adjusted to 7.6-8.2 by lowering the pH by adding 0.1 N hydrochloric acid solution.

[0494] b) 0.147 g of Ca-BT-DO3A [ie 0.1% mol / mol relative to the total Gd concentration] was added and dissolved while stirring.

[0495] c) Gd of 193.4g (ie 0.075M) formula (I-a) 4 The -DO3A-derived tetrachelate is added to the solution obtained in step b) and dissolved while stirring.

[0496] d) Add 4.4 g of sodium chloride to the solution obtained in step c) and dissolve while stirring.

[0497] e) Adjust the pH of the solution obtai...

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Abstract

The present disclosure relates to a liquid pharmaceutical formulation comprising a DOSA-derived tetra-chelate of formula (I), in which M is an ion of a paramagnetic metal, preferably a Gd3+ ion, and R1, R2, R3, R4 and R5 are as defined in the claims, in a pharmaceutical acceptable solvent. The present disclosure also relates to a method of preparation of said liquid pharmaceutical formulation and to a method of imaging involving said liquid pharmaceutical formulation.

Description

[0001] The present invention relates to preparations of contrast agents, in particular paramagnetic metal ion chelators, in particular for magnetic resonance imaging, and to an industrially applicable process for obtaining said preparations. Background technique [0002] Various contrast agents based on lanthanide (paramagnetic metal) chelates, especially gadolinium chelates, such as those described in the document US Pat. No. 4,647,447, are known. These products are called GBCAs (gadolinium-based contrast agents). Several GBCAs are approved for clinical use and are commercially available: notably linear Gd-chelates such as gadopentetate dimeglumine ( DTPA based), gadodiamide ( Based on DTPA-BMA), gadofurcetamide ( based on DTPA-BMEA), and in particular, the macrocyclic Gd-chelate, gadoterate meglumine ( based on DOTA), gadoteridol ( Based on HP-DO3A), gadobutrol ( Based on BT-DO3A, Butrol), gadoxetic acid ( Based on EOB-DTPA) and gadobenate meglumine ( Based on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/12A61K49/08A61K49/10
CPCA61K49/124A61K49/106A61K49/085A61K49/18A61K49/108
Inventor S.霍尔兹舒T.弗伦泽尔G.乔斯特J.洛尔克W.埃伯特T.布伦比W.哈夫布罗特
Owner BAYER AG