Pharmaceutical Contrast Agent Formulation Free Chelate Control
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Solution Overview
Problem
Current pharmaceutical formulations of contrast agents based on lanthanide chelates, particularly gadolinium, face challenges in tolerance due to potential release of free lanthanide ions, which can lead to adverse reactions and conditions like nephrologic systemic fibrosis (NSF), necessitating improved control over the concentration of free chelates and lanthanides in the formulations.
Innovation Solution
A process involving measurement and adjustment of free macrocyclic chelate and lanthanide concentrations in the pharmaceutical formulation to achieve a specific range of 0.002% to 0.4% free macrocyclic chelate, ensuring the scavenging capacity for free gadolinium and stability, while minimizing industrial production complexities and costs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If excess free macrocyclic chelate is added to the formulation, then the scavenging capacity for free gadolinium is improved, but the toxicity increases
Solution Approach 1:
The patent applies parameter changes by precisely controlling the concentration of free macrocyclic chelate within a specific range (0.002% to 0.4%). This quantitative parameter optimization allows the formulation to maintain adequate scavenging capacity while limiting toxicity, resolving the contradiction between these two opposing requirements.
2Reliability
If measurement and adjustment steps are implemented to control free chelate concentration, then the safety and tolerance are improved, but the manufacturing complexity increases
Solution Approach 1:
The patent implements preliminary action by pre-calculating and pre-mixing the exact amounts of free macrocyclic chelate and lanthanide complex required to achieve the target concentration range. This advance preparation eliminates the need for complex real-time measurement and adjustment equipment during manufacturing, reducing process complexity while maintaining safety.
3Reliability
If the concentration of free macrocyclic chelate is precisely controlled within a narrow range, then the tolerance is improved, but the manufacturing precision requirements increase
Solution Approach 1:
The patent defines a specific concentration range (0.002% to 0.4%) for free macrocyclic chelate that balances tolerance improvement with achievable manufacturing precision. By establishing this quantitative parameter boundary, the patent makes precise concentration control feasible through standard pharmaceutical manufacturing techniques.
4Stability of the object's composition
If excess chelate is added to compensate for lanthanide release, then the stability is improved, but the formulation complexity increases
Solution Approach 1:
The patent makes the free macrocyclic chelate serve multiple functions simultaneously: it acts as a stabilizing agent to prevent lanthanide release, provides scavenging capacity for free gadolinium, and maintains formulation stability. This multi-functionality reduces the need for additional separate components, thereby reducing overall formulation complexity while improving stability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process ensures high tolerance and stability of the pharmaceutical formulation by precisely controlling the concentration of free macrocyclic chelate, significantly enhancing the scavenging capacity for free gadolinium, thereby reducing the risk of adverse reactions and improving the safety and efficacy of the contrast agents.
Implementation Method 1
an amount of free macrocyclic chelate, so that the pharmaceutical composition to be administered contains between 0.002% and 0.4% of free macrocyclic chelate which is not under the form of an excipient... the excess chelate then complexing with the released lanthanide
Data Source
AI summary
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 of free macrocyclic chelate of between 0.002% and 0.4%, said process comprising the following successive steps: b) preparation of a liquid pharmaceutical composition containing the complex of macrocyclic chelate with a lanthanide, free macrocyclic chelate that is not under the form of an excipient X[X',L] in which L is the macrocyclic chelate and X and X' are a metal ion, in particular chosen independently from calcium, sodium, zinc and magnesium, and/or free lanthanide, said step b) consisting in the preparation of a solid complex [chelate-lanthanide] and in the dissolution of the said complex in water ; c) measurement in the pharmaceutical formulation obtained in step b) of the concentration of free macrocyclic chelate Cch 1 or of free lanthanide Clan 1; d) adjustment of Cch 1 and/or of Clan 1 by adding to the formulation obtained in step b) : - if Clan 1 > 0 and/or Cch 1 < Ct ch 1, free macrocyclic chelate, - if Clan 1 = 0 and Cch 1 > Ct ch 1, free lanthanide, so as to obtain Cch 1 = Ct ch 1 and Clan 1 = 0 wherein Ct ch 1 is the target concentration of the free macrocyclic chelate in the final liquid pharmaceutical formulation and is selected in the range of between 0.002 % and 0.4 % mol/mol, wherein the amount of free macrocyclic chelate in the final liquid pharmaceutical formulation corresponds to the proportion of free macrocyclic chelate relative to the amount of complexed macrocyclic chelate in the final liquid pharmaceutical formulation.