Process for preparing a pharmaceutical formulation of contrast agents
a technology of contrast agent and pharmaceutical formulation, which is applied in the direction of drug composition, pharmaceutical delivery mechanism, heavy metal compound active ingredients, etc., can solve the problems of fibrogenic dermopathy, severe effects on human skin, and complex tolerance still exists
Inactive Publication Date: 2016-08-18
GUERBET SA
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Problems solved by technology
Despite all these prior-art studies, the complex problem of tolerance still exists, especially in situations at risk of more pronounced tolerance for the administration of MRI contrast products.
A new problem has moreover recently appeared in the matter of tolerance, namely a pathology known as NSF (nephrologic systemic fibrosis, or fibrogenic dermopathy, with very severe effects on human skin), which may be at least partly correlated to the existence of free gadolinium, i.e. non-complexed gadolinium, in the body.
Briefly, NSF could be associated to the transmetallation of some lanthanide from the complex [lanthanide-chelate] by endogenic ions such as zinc and resulting in unwanted release of free lanthanide.
In summary, this problem of tolerance of complexes of chelates with lanthanides remains complex and important, leading to the research of even more safe products, and to the necessity of a perfectly controlled rate of the different entities in the pharmaceutical solutions.
Consequently, in view of this low amount of free excess, a new problem arises, which is unknown in the prior art, namely the need for extremely precise and delicate industrial-scale control of the concentrations of free macrocyclic chelate and thus of the manufacture of the product to arrive at this range of target values of amount of free chelate, these values needing to be stable, including after storage for several months or years.
In particular, the Applicant found that the mixing of stoichiometric amounts on the basis of the theoretical calculation does not sufficiently satisfactorily give at the industrial scale the respective amounts of complex of chelate with the lanthanide and of free chelate in low concentration in the pharmaceutical formulation.
The reason for this is that it is then necessary to perform several analysis steps, which takes sev
Method used
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[0182]1) Example 1: In Vivo Tolerance
[0183]The tolerance results in Table 2 (acute toxicity in mice for a diagnostic solution of DOTA; this solution is a pharmaceutical solution injected and comprising the complex of DOTA with the Gd3+, and an excess of free DOTA not complexed by Gd3+ and not complexed by metal ions as excipient) show that formulations containing from 0.025 to 0.25 mot / mol % of free macrocyclic chelate DOTA are three times less toxic than the formulation close to 2%.
Excess of FreeDOTAMale LD50Female LD50Testmol / mol %Mmol / kgMmol / kg10.0512.4113.5920.0913.0613.5030.2512.0212.0741.984.804.80
[0184]Further stability studies performed by the Applicant show that the formulations are very satisfying with no release of gadoninium for a long conservation time.
[0185]Example 2: Process for Preparing Formulations of Lanthanide Chelate (Mixture of a Solution of Chelate and of a Solution of Lanthanide)
[0186]The preparation of formulations in which the macrocyclic chelate is DOTA is...
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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 Cch1 and/or of free lanthanide Clan1; d) adjustment of Cch1 and/or of Clan1 so as to obtain Cch1=Ct ch1 and Clan1=0, wherein ct ch1 is the target concentration of free macrocyclic chelate in the final liquid pharmaceutical formulation.
Description
[0001]The invention relates to pharmaceutical formulations of contrast agents, in particular of complexes of chelates with paramagnetic metal ions, especially for magnetic resonance imaging, and to industrially efficient processes for obtaining these formulations.[0002]Many contrast agents based on complexes of chelates with lanthanides (paramagnetic metal), in particular with gadolinium, are known, and are described, for example, in document U.S. Pat. No. 4,647,447. Several products are marketed, 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 the body, the complexes of chelates with lanthanide are in a situation of chemical equilibrium, which may lead to a risk of undesired release of the lanthanide, and more especially of gadolinium. A person skilled in the art is thus led ...
Claims
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Patent Timeline
Login to View More IPC IPC(8): A61K49/10A61K9/00
CPCA61K49/106A61K9/0019A61K45/06A61K49/108A61K31/28A61P43/00A61K47/18G01N33/15
InventorMEYER, DOMINIQUECOROT, CLAIREPORT, MARCBARBOTIN, VINCENTBONNEMAIN, BRUNO
OwnerGUERBET SA