RNA Buffer System Using Triethanolamine for Stability
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Solution Overview
Problem
Current RNA nanoparticle formulations, particularly those with ionizable lipids, face challenges in stability and shelf life, requiring freezing at low temperatures or limited stability at room temperature, and are prone to RNA fragmentation and stable folded forms that hinder accessibility for translation.
Innovation Solution
The use of a specific buffer system comprising triethanolamine (TEA) and its protonated form inhibits the formation of stable folded RNA forms, allowing for improved RNA integrity and stability at temperatures between +2 and +20°C, enabling storage and repeated freezing/thawing without significant degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If RNA is stored in liquid form at temperatures between +2 and +20°C, then ease of operation and readiness for use is improved, but RNA stability and shelf life deteriorate due to fragmentation and formation of stable folded forms
Solution Approach 1:
The patent applies parameter changes by modifying the chemical composition parameters of the storage medium. Specifically, it replaces conventional buffers (like PBS) with a novel buffer system comprising triethanolamine (TEA) and its protonated form at specific concentrations and pH ranges (pH 6.5-7.5). This chemical parameter change prevents RNA fragmentation and stable folded form formation, enabling RNA to maintain stability in liquid form at refrigeration temperatures (+2 to +8°C) for extended periods (at least 3 months), thus resolving the contradiction between ease of operation and RNA stability
Solution Approach 2:
The patent employs composite materials by creating a composite buffer system that combines multiple components: triethanolamine (TEA), its protonated form, and specific salt concentrations (NaCl, KCl, CaCl2, MgCl2). This composite buffer composition works synergistically to maintain RNA stability in liquid formulations. The composite nature of the buffer system provides multiple protective mechanisms simultaneously, allowing RNA therapeutic compositions to be stored in liquid form at refrigeration temperatures without degradation, thereby improving both ease of operation and maintaining RNA stability
2Stability of the object's composition
If RNA nanoparticle formulations are frozen at low temperatures (e.g., -80°C) for stabilization, then RNA stability is improved, but device complexity and cold chain requirements worsen
Solution Approach 1:
The patent applies parameter changes by fundamentally altering the storage temperature parameter from ultra-low freezing temperatures (-80°C) to refrigeration temperatures (+2 to +8°C). This is achieved through chemical parameter modification of the buffer system (using TEA and its protonated form at specific concentrations and pH). The parameter change eliminates the need for complex frozen cold chain infrastructure while maintaining RNA stability, thus resolving the contradiction between RNA stability and cold chain complexity
Solution Approach 2:
The patent enables RNA therapeutic compositions to be stored as stable liquid formulations at refrigeration temperatures without requiring freezing. This transforms the storage requirement from a complex, expensive frozen state to a simpler, more accessible refrigerated liquid state. The composition can be stored in standard refrigerators (+2 to +8°C) for at least 3 months, eliminating the need for ultra-low temperature freezers and complex frozen cold chain logistics, thereby reducing device complexity and infrastructure requirements
3Stability of the object's composition
If conventional buffers (e.g., PBS) are used for RNA storage, then RNA adopts a stable folded form, but this stable folded form is hardly accessible for translation
Solution Approach 1:
The patent applies parameter changes by modifying the buffer chemical composition from conventional PBS to a TEA-based buffer system with specific pH (6.5-7.5) and ionic strength parameters. This parameter change prevents RNA from adopting overly stable folded forms that are inaccessible for translation. The TEA buffer system maintains RNA in a conformation that is both stable and translationally accessible, resolving the contradiction between folded form stability and translation accessibility
Solution Approach 2:
The patent uses triethanolamine (TEA) and its protonated form as intermediary substances that mediate between RNA stability and translation accessibility. The TEA buffer system acts as an intermediary chemical environment that prevents excessive folding while maintaining structural integrity. This intermediary buffer composition allows RNA to maintain a balanced conformation that is sufficiently stable for storage but remains accessible for cellular translation machinery, thus resolving the contradiction
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 buffer system maintains RNA integrity for up to three months in liquid form at room temperature, providing a stable and ready-to-use composition compliant with regular pharmaceutical storage conditions.
Implementation Method 1
the aqueous phase comprises a buffer system comprising a buffer substance having the formula N(R1)(R2)(R3), its N-oxide, or a protonated form thereof
Data Source
AI summary
The present disclosure relates generally to the field of RNA compositions comprising a buffer substance, methods for preparing and storing such compositions, and the use of such compositions in therapy.