mRNA LNP Formulation via pH Optimization for Microneedle Delivery
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Solution Overview
Problem
Existing mRNA compositions for microneedle administration have low drug loading capacity, leading to high doses and toxic side effects, and are limited by the need for large injection volumes, making them unsuitable for effective microneedle delivery due to limitations in target selectivity, stability, and immune response.
Innovation Solution
A high mRNA-loaded composition is developed using a lipid solution encapsulating an aqueous phase solution with a pH of 4.5-6.8 to form lipid nanoparticles (LNPs), which increases drug loading capacity, reduces toxicity, and enhances therapeutic effects by targeting specific tissues with improved immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If existing mRNA compositions are injected intravenously or intramuscularly, then the drug can be delivered into the body, but the injection volume required is large (>50 μL), causing potential vascular damage, inflammation, injection pain, and low nucleic acid expression
Solution Approach 1:
The patent optimizes the pH of the aqueous phase solution from conventional ranges to 4.5-6.8, which significantly increases mRNA loading capacity in LNPs. This parameter change allows reduction of injection volume to ≤50 μL while maintaining therapeutic efficacy, thereby avoiding vascular damage and inflammation associated with large-volume injections
Solution Approach 2:
The patent uses lipid nanoparticles (LNPs) as a composite delivery system comprising ionizable lipids, phospholipids, cholesterol, and PEGylated lipids. This composite structure enables high mRNA loading capacity in small volumes, protecting the mRNA while delivering it efficiently at volumes ≤50 μL to avoid injection-related harm
2Ease of operation
If existing mRNA compositions are injected intramuscularly or subcutaneously, then the injection is easier to administer, but the drug utilization is low and the onset of action is slow
Solution Approach 1:
The patent adjusts the pH of the aqueous phase to 4.5-6.8, which enhances mRNA loading capacity and stabilizes the LNP structure. This optimization improves drug utilization efficiency by ensuring more mRNA is delivered to target cells, accelerating onset of action while maintaining ease of intramuscular or subcutaneous administration
Solution Approach 2:
The LNP acts as an intermediary carrier that protects mRNA from degradation and facilitates its cellular uptake. The optimized pH-dependent LNP formulation enhances this intermediary function, improving drug utilization efficiency and onset speed while keeping the administration route simple
3Reliability
If existing LNP formulations are used, then the mRNA can be protected from degradation, but the LNP components are non-natural compounds that may cause irritation or toxicity in humans
Solution Approach 1:
The patent optimizes the pH of the aqueous phase to 4.5-6.8, which enhances mRNA loading efficiency and promotes formation of stable LNPs with reduced toxicity. This pH optimization allows use of lower LNP component concentrations, reducing irritation and toxicity while maintaining mRNA protection
Solution Approach 2:
The patent uses ionizable lipids that exhibit different properties at different pH levels. At acidic pH (4.5-6.8) during formulation, they provide high mRNA binding and protection. At physiological pH, they become less aggressive, reducing toxicity. This local quality change resolves the contradiction between protection and toxicity
4Ease of manufacture
If the pH of the aqueous phase solution is not optimized, then the formulation is simpler, but the mRNA loading capacity is low, requiring high doses that increase toxic side effects
Solution Approach 1:
The patent identifies and optimizes the pH parameter of the aqueous phase to 4.5-6.8, which dramatically increases mRNA loading capacity in LNPs. This single parameter optimization achieves high loading capacity without complicating the formulation process, allowing low-dose administration and reducing toxic side effects
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 composition achieves stable long-term storage, significant immune effects, and tumor inhibitory effects through microneedle administration, reducing liver expression and toxicity while increasing antibody titers and therapeutic efficacy at lower doses.
Implementation Method 1
the lipid solution encapsulates the substance in the aqueous phase solution to form LNPs
Implementation Method 2
said microneedle can create microchannels in the Stratum corneum of the skin, break through the Stratum corneum barrier and promote drug penetration
Data Source
AI summary
The present invention provides a mRNA composition for microneedle administration and its application. The composition includes an aqueous phase solution and a lipid solution, wherein the lipid solution encapsulates the substance in the aqueous phase solution to form lipid nanoparticles (LNPs), and the aqueous phase solution includes mRNA encoding the corresponding protein and a buffer. It was found that an improved buffer pH could substantially increase the drug loading capacity of LNPs, and reduce the use level of composition and excipients and the dose for microneedle administration with less toxic side effects and better therapeutic effects, and the microneedle administration technology could achieve increased effective expression, decreased expression in the liver, and prolonged in vivo expression of mRNA composition, and increased antibody titer in response to low-dose mRNA in vivo. The present invention really realizes microneedle intradermal administration of mRNA composition. The composition for microneedle intradermal administration enables stable long-term storage, and has a potential application prospect of reducing toxicity and increasing efficacy.