Bortezomib Mannitol Ester Aqueous Solution Stability
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Solution Overview
Problem
Bortezomib, a proteasome inhibitor used for treating multiple myeloma and mantle cell lymphoma, faces stability issues in aqueous solutions due to oxidation sensitivity and requires a safer, more stable ready-to-use liquid form for improved physiological tolerance.
Innovation Solution
A ready-to-use liquid pharmaceutical solution comprising bortezomib in the form of an ester dissolved in an aqueous solvent, with a preferred composition of at least 50% water and containing bortezomib polyol esters, which maintains stability for extended periods without the use of harmful organic solvents like propylene glycol.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If bortezomib is formulated as a ready-to-use aqueous solution, then physiological tolerance is improved, but stability deteriorates due to oxidation sensitivity
Solution Approach 1:
The patent uses mannitol as an intermediary substance that reacts with bortezomib to form a stable ester derivative. This intermediary compound protects bortezomib from oxidation in aqueous solutions while maintaining physiological compatibility. The mannitol ester acts as a stable precursor that releases active bortezomib at the administration site, resolving the contradiction between aqueous stability and oxidation sensitivity.
Solution Approach 2:
The patent changes the chemical parameter of bortezomib by converting it from the free acid form to an esterified form with mannitol. This parameter change (esterification) fundamentally alters the chemical stability profile, making the compound resistant to oxidation in aqueous environments while maintaining its pharmacological activity upon administration.
2Stability of the object's composition
If organic solvents like propylene glycol are used to improve stability, then stability is improved, but harmful effects worsen due to liver and kidney damage
Solution Approach 1:
The patent changes the solvent parameter from organic solvents (propylene glycol) to an aqueous-based system. This parameter change eliminates the toxic effects of organic solvents on liver and kidney while maintaining stability through the esterification of bortezomib with mannitol, which provides oxidation protection in the aqueous environment.
Solution Approach 2:
The patent extracts and eliminates the harmful organic solvent component from the formulation. By removing propylene glycol and other organic solvents, the patent eliminates the associated hepatotoxicity and nephrotoxicity, replacing the stability mechanism with a chemically modified bortezomib derivative that is inherently stable in water.
3Quantity of substance
If bortezomib mannitol ester is used in solution, then solubility is improved, but stability worsens due to hydrolysis equilibrium
Solution Approach 1:
The patent applies local quality by creating a specific molecular structure where mannitol is esterified with bortezomib at specific hydroxyl groups. This localized chemical modification at specific sites on the bortezomib molecule creates a stable ester bond that does not readily hydrolyze, while the remaining mannitol hydroxyl groups maintain aqueous solubility. The local structural arrangement prevents the unfavorable hydrolysis equilibrium.
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 solution provides improved physiological tolerance and stability, maintaining bortezomib content above 90% for several months at various temperatures, ensuring safe and effective administration without adverse reactions.
Implementation Method 1
bortezomib mannitol ester in solution is in equilibrium with its hydrolysis products, free bortezomib and mannitol
Data Source
AI summary
The present invention relates to a ready-to-use liquid pharmaceutical bortezomib solution. To provide a bortezomib solution of the generic type exhibiting improved physiological tolerance, a ready-to-use liquid pharmaceutical solution is proposed, comprising: - an aqueous solvent; - a bortezomib derivative dissolved in the solvent.