Flagellin Aerosol Stabilization via Buffer and Surfactant
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Solution Overview
Problem
The challenge lies in developing a stable aerosol composition for pulmonary delivery of flagellin polypeptides that maintains their biological activity and stability during aerosolization, as they are prone to aggregation and degradation due to shear stress and temperature changes, which is crucial for effectively treating lung bacterial infections.
Innovation Solution
Aerosol compositions comprising flagellin polypeptides with acetate or phosphate buffers and polysorbate surfactants, formulated to maintain a pH of 8 or lower, which reduces aggregation and enhances stability during nebulization, ensuring effective delivery and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If flagellin is formulated in saline phosphate buffer (PBS) for pulmonary delivery, then the protein can be administered to the lungs, but the flagellin undergoes high aggregation and loss of biological activity due to aerosolization stress
Solution Approach 1:
The patent changes the buffer system from PBS to acetate buffer, adjusts pH to 4.0-6.0 range, and optimizes flagellin concentration to 1-10 mg/mL. These parameter changes fundamentally alter the formulation properties to prevent aggregation during aerosolization while maintaining pulmonary delivery capability and flagellin biological activity
Solution Approach 2:
The patent introduces specific excipients as intermediaries: acetate buffer acts as a pH mediator to maintain stable conditions, and polysorbate 80 serves as a surfactant mediator that prevents protein-protein interactions and aggregation during the aerosolization process, thereby protecting flagellin stability
2Productivity
If the aerosolization process is performed with standard formulations, then the flagellin can be delivered to the lungs, but the protein experiences shear stress and temperature changes leading to degradation
Solution Approach 1:
The patent applies prior cushioning by incorporating polysorbate 80 surfactant and optimizing the buffer system before aerosolization occurs. These pre-formulation protections cushion the flagellin against the impending shear stress and temperature changes during nebulization, preventing degradation while maintaining delivery efficiency
3Device complexity
If flagellin is nebulized without optimized formulation, then the administration process is simple, but the protein exhibits decreased stability at the air-liquid interface
Solution Approach 1:
The patent introduces polysorbate 80 as a surfactant intermediary that specifically addresses the air-liquid interface problem. This surfactant reduces surface tension and prevents flagellin aggregation at the interface during nebulization, maintaining stability without significantly complicating the formulation or administration process
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 effectively stabilizes flagellin polypeptides, maintaining their potency and reducing aggregation, thereby ensuring effective pulmonary delivery and treatment of lung bacterial infections.
Implementation Method 1
a surfactant consisting of polysorbate
Implementation Method 2
proteins can be sensitive towards aerosolization-associated shear stress and/or increase in temperature and/or may exhibit decreased stability at the air-liquid interface in an aerosol
Implementation Method 3
a buffering agent selected from the group consisting of acetate, phosphate and combinations thereof; wherein the liquid formulation has a pH which is equal to or lower than about 8
Data Source
AI summary
The present invention arises from a formulation study in order to define the best excipients including buffer, surfactant, sugar and amino acid to stabilize Flagellin during mesh-nebulization. One of the key factors in stabilising proteins is determining the optimal pH and buffer system to provide adequate solubility and stability and avoid aggregate formation during the aerosolization process. Different formulation have been assayed in order to obtain a stable and soluble aerosol composition comprising flagellin polypeptide in particular considering the choice of the buffering agent, the surfactant and the pH of the liquid formulation comprising the flagellin polypeptide in order to maintain the activity of the flagellin after the aerosolization process. Accordingly, the present invention relates to an aerosol composition comprising droplets comprising a liquid formulation, wherein the liquid formulation comprises a flagellin polypeptide, a buffer (acetate and/or phosphate) and a surfactant (polysorbate).The aerosol composition of the present invention is suitable for the treatment of lung bacterial infections.