TBA-Modified Lyophilized Polypeptide Formulations for Faster Reconstitution
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Solution Overview
Problem
High-concentration and high-dose lyophilized pharmaceutical products, such as antibody compositions, face challenges with long reconstitution times and stability issues, particularly when using tert-butyl alcohol (TBA) in formulations for small quantities or low-doses, which are not well-characterized for large quantities or high concentrations.
Innovation Solution
Incorporating tert-butyl alcohol (TBA) into lyophilized polypeptide formulations at specific concentrations, typically between 0.5% to 20% by volume, along with a sugar-to-protein molar ratio of at least 360:1, to reduce reconstitution times by freezing and lyophilizing the mixture, followed by reconstitution with a diluent.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If high-concentration and high-dose lyophilized formulations are used, then the fill volume is reduced and multiple vials are needed, but the reconstitution time becomes excessively long
Solution Approach 1:
TBA serves as an intermediary substance that mediates between the high-concentration protein formulation and the reconstitution process. It acts as a cosolvent that facilitates rapid dissolution of the lyophilized cake when diluent is added, enabling fast reconstitution even at high protein concentrations without requiring multiple vials
Solution Approach 2:
The invention changes the physical-chemical parameters of the formulation by incorporating TBA at specific concentrations (0.5-20% v/v) and adjusting the sugar-to-protein molar ratio (at least 360:1). These parameter modifications create a lyophilized cake with optimized porosity and solubility characteristics that enable rapid reconstitution at high concentrations
2Loss of time
If TBA is added to lyophilized formulations to reduce reconstitution time, then reconstitution time decreases, but the stability and integrity of the polypeptide may be compromised
Solution Approach 1:
The invention optimizes the concentration parameters of TBA (0.5-20% v/v) and the sugar-to-protein molar ratio (at least 360:1) to achieve the right balance. These parameter adjustments ensure that TBA provides sufficient cosolvent effect for rapid reconstitution while maintaining polypeptide stability through appropriate sugar protection
Solution Approach 2:
The formulation creates a composite system combining TBA, sugar (at least 360:1 molar ratio to protein), and polypeptide. This composite formulation leverages the cosolvent properties of TBA for rapid reconstitution while the sugar component provides protective effects that maintain polypeptide integrity and stability during storage and reconstitution
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 method significantly reduces reconstitution times by 40% to 95% compared to formulations without TBA, maintaining the integrity and stability of the lyophilized polypeptides, especially antibody compositions.
Implementation Method 1
adding tert-butyl alcohol (TBA) to the liquid composition to form a liquid polypeptide/TBA mixture
Implementation Method 2
freezing the liquid polypeptide/TBA mixture
Implementation Method 3
lyophilizing the liquid polypeptide/TBA mixture to form a lyophilized polypeptide composition
Implementation Method 4
placed under vacuum
Implementation Method 5
reconstituting the lyophilized polypeptide composition with a diluent
Data Source
AI summary
The present invention relates to methods and formulations useful for reducing the reconstitution time of lyophilized polypeptides.