AAV Formulation Stability via Buffering and Surfactant Mediation
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Solution Overview
Problem
Current AAV formulations for human administration face challenges in maintaining long-term stability, preventing adsorption to surfaces, and minimizing potency loss during manufacturing and storage, despite efforts to design safe and effective formulations.
Innovation Solution
The development of pharmaceutical compositions comprising AAV, buffering agents, pharmaceutically acceptable salts, non-ionic surfactants, and sugars or sugar alcohols, which are formulated to prevent adsorption and maintain potency, including specific concentrations of L-histidine, sodium chloride, polysorbate 80, and sucrose or trehalose, and can be either liquid or lyophilized for enhanced stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If AAV formulations are designed for long-term storage, then stability is improved, but adsorption to container surfaces and potency loss occur
Solution Approach 1:
The patent introduces a specific formulation composition including buffering agents (pH 6.0-8.0), salts (50-150 mM), non-ionic surfactants (0.001-0.01% w/v), and sugars or sugar alcohols (1-10% w/v) as intermediary substances that mediate between the AAV and the storage environment, preventing direct harmful interactions with container surfaces while maintaining viral stability during long-term storage
Solution Approach 2:
The patent optimizes specific formulation parameters including pH (6.0-8.0), salt concentration (50-150 mM), surfactant concentration (0.001-0.01% w/v), and sugar/sugar alcohol content (1-10% w/v) to achieve the optimal balance between stability and prevention of potency loss, demonstrating that precise parameter control resolves the contradiction
2Stability of the object's composition
If AAV formulations use high salt concentrations, then stability is improved, but adsorption to surfaces increases
Solution Approach 1:
The patent identifies and optimizes the salt concentration parameter within a specific range (50-150 mM) to achieve optimal stability while minimizing surface adsorption, demonstrating that precise parameter control resolves the contradiction between stability and adsorption
3Duration of action of stationary object
If AAV formulations are stored for extended periods, then long-term stability is achieved, but visible particle formation occurs
Solution Approach 1:
The patent introduces sugars or sugar alcohols (1-10% w/v) and non-ionic surfactants as intermediary protective agents that prevent direct aggregation and visible particle formation during extended storage periods, allowing long-term stability without degradation
Solution Approach 2:
The formulation includes protective agents (sugars, sugar alcohols, surfactants) that provide beforehand cushioning against degradation mechanisms, preventing visible particle formation before it can occur during extended storage
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
These formulations effectively prevent visible particle formation, reduce degradation, and maintain significant AAV activity over extended periods, ensuring stability and potency during storage and administration.
Implementation Method 1
about 5 mM to about 25 mM of a buffering agent
Implementation Method 2
about 0.001% (w/v) to about 0.01% (w/v) of a non-ionic surfactant
Implementation Method 3
about 1% (w/v) to about 10% (w/v) of a sugar or sugar alcohol
Data Source
AI summary
Adeno-associated liquid and lyophilized pharmaceutical compositions are provided herein. In exemplary aspects, the pharmaceutical compositions comprise about 5 mM to about 25 mM L-histidine, about 0 mM to about 150 mM sodium chloride, about 0.001% (w/v) to about 0.01% (w/v) polysorbate 80 (PS80), and about 1% to about 10% (w/v) sucrose, trehalose, or combination thereof to AAV. In exemplary aspects, the pharmaceutical compositions further comprise glycine or mannitol. Methods of preparing a pharmaceutical composition comprising AAV, methods of treating a bleeding disorder in a subject, and methods of storing AAV compositions are also provided.