Bortezomib Formulation Stability via Non-Aqueous Solvents
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Solution Overview
Problem
Current bortezomib formulations are unstable in solution, leading to rapid degradation and limited storage stability, which restricts their use in multi-dose liquid formulations and flexible dosing options.
Innovation Solution
Development of a substantially non-aqueous liquid formulation with propylene glycol as the main solvent and a hetero-bifunctional Lewis base to form a Lewis donor-acceptor complex, which stabilizes bortezomib and suppresses degradation products, allowing for extended storage stability and multi-dose applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If bortezomib is formulated in aqueous solution for injection, then it is ready for administration, but it degrades rapidly and loses stability during storage
Solution Approach 1:
The patent changes the fundamental parameter of the solvent system from aqueous to non-aqueous (using propylene glycol, polyethylene glycol, or their mixtures). This parameter change transforms the formulation from unstable in water to stable in non-aqueous environment, allowing the solution to maintain bortezomib integrity during storage while remaining ready for administration.
Solution Approach 2:
The patent uses composite solvent systems combining propylene glycol and polyethylene glycol in specific ratios. This composite approach leverages the stabilizing properties of both glycols to create a formulation that provides enhanced storage stability while maintaining the desired ease of administration.
2Productivity
If bortezomib is stored in solution form, then it is readily available for dosing, but it undergoes spontaneous degradation and rearrangement
Solution Approach 1:
The patent changes the chemical environment parameter by replacing water-based solvents with non-aqueous glycol-based solvents. This parameter change suppresses the spontaneous 1,3-rearrangement and oxidative degradation reactions that occur in aqueous solutions, thereby improving reliability while maintaining dosing flexibility.
Solution Approach 2:
The non-aqueous glycol solvent system creates an inert chemical environment that protects bortezomib from degradation reactions. This inert environment prevents water-mediated hydrolysis and oxidation, ensuring the compound remains chemically stable and reliable for extended storage periods.
3Ease of manufacture
If conventional solvent systems are used to dissolve bortezomib, then the formulation is simple to prepare, but the compound degrades within hours or days
Solution Approach 1:
The patent modifies the solvent composition parameter by using propylene glycol and/or polyethylene glycol instead of conventional aqueous solvents. This change extends the storage duration from hours/days to months while maintaining ease of manufacture, as the formulation process remains straightforward and does not require complex processing steps.
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 formulation maintains bortezomib stability at less than 10 wt% degradation over three months at ambient conditions, enabling the creation of storage-stable, multi-dose liquid bortezomib formulations suitable for extended use.
Implementation Method 1
a hetero-bifunctional Lewis base to form a Lewis donor-acceptor complex, which stabilizes bortezomib and suppresses degradation products
Implementation Method 2
bortezomib was reported to be susceptible to oxidative degradation under a number of experimental conditions... a substantially non-aqueous solvent system suitable for injection... stabilizes bortezomib and suppresses degradation products
Data Source
AI summary
Multi-dose formulations for bortezomib are presented in which bortezomib has significantly improved stability. Especially preferred formulations include those in which bortezomib is in a liquid form suitable for injection, wherein the solvent system predominantly comprises propylene glycol. In other preferred aspects, bortezomib is present as a Lewis donor-acceptor complex with a hetero-bifunctional Lewis base.