Cyclodextrin Formulation Strategy for Polysorbate Degradation
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Solution Overview
Problem
Polysorbate degradation in pharmaceutical formulations poses challenges during processing, long-term storage, and administration, leading to reduced stability and shelf-life of protein drugs, with enzymatic degradation being a significant issue that existing technologies have not adequately addressed.
Innovation Solution
Incorporating cyclodextrin into aqueous formulations at a ratio greater than 37.5:1 with polysorbate helps reduce degradation, disaggregate, and solubilize polysorbate degradation products, maintaining the protective effects of polysorbate on formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polysorbate is used as a surfactant in pharmaceutical formulations, then protein stability is improved by preventing surface-induced denaturation and aggregation, but polysorbate degradation occurs leading to particle formation and loss of protective effects
Solution Approach 1:
Cyclodextrin acts as an intermediary substance that binds to polysorbate degradation products (fatty acids) through host-guest complexation. This prevents the degradation products from aggregating into particles while allowing the cyclodextrin to sequester and solubilize the harmful degradation products, thereby maintaining protein stability despite polysorbate degradation
Solution Approach 2:
The invention converts the harmful polysorbate degradation products (fatty acids that cause particle formation) into beneficial soluble complexes through cyclodextrin inclusion. The degradation products that would normally reduce reliability are transformed into soluble, non-particle-forming complexes, thus converting a harmful effect into a beneficial one
2Reliability
If polysorbate is used to protect proteins during processing and storage, then protein aggregation is prevented, but polysorbate degrades via hydrolytic and oxidative pathways reducing shelf-life
Solution Approach 1:
Cyclodextrin serves as a mediator that intercepts and binds polysorbate degradation products through inclusion complexation. This prevents the accumulation of free fatty acids that would otherwise lead to particle formation and formulation instability, thereby extending the duration of protective action
Solution Approach 2:
The invention changes the physical-chemical parameters of the degradation products by forming inclusion complexes with cyclodextrin. This transforms the degradation products from a harmful state (free fatty acids causing aggregation) to a beneficial state (solubilized complexes), effectively extending formulation shelf-life
3Stability of the object's composition
If antioxidants are added to prevent polysorbate oxidation, then oxidative degradation is reduced, but hydrolytic degradation pathways remain active
Solution Approach 1:
Cyclodextrin acts as a universal intermediary that binds to both oxidative and hydrolytic degradation products of polysorbate. Rather than trying to prevent degradation through multiple different mechanisms, the cyclodextrin intercepts the products of both degradation pathways, providing comprehensive protection against both oxidation and hydrolysis
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 polysorbate degradation by up to 99%, stabilizes formulations for extended periods, and minimizes the formation of visible and subvisible particles, thereby enhancing the shelf-life and stability of protein drugs.
Implementation Method 1
adding a cyclodextrin to the formulation, wherein the resulting w/w ratio of cyclodextrin to polysorbate is greater than about 37.5:1
Data Source
AI summary
The invention provides methods for making such formulations and methods of using such formulations. The invention further provides methods of reducing polysorbate degradation, methods of reducing the amount of visible and sub-visible particles in an aqueous formulation, and methods of disaggregating polysorbate degradation products comprising adding a cyclodextrin to a formula comprising polysorbate and a polypeptide. The invention also provides aqueous formulations comprising a polypeptide, a polysorbate, and a cyclodextrin with reduced polysorbate degradation.