Spray-Dried mRNA Lipid Powders With Polymer Thermal Stabilization

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Solution Overview

Problem

Current mRNA formulations are typically in liquid form and require invasive administration methods like injections or nebulizers, and lyophilized powders lack uniformity and stability, leading to mRNA degradation and instability during handling and storage.

Innovation Solution

A dry powder formulation of mRNA encapsulated with lipid-based nanoparticles, stabilized by the addition of a polymer, which prevents aggregation during spray-drying and maintains mRNA integrity and encapsulation efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Shape

If spray-drying is performed at high temperatures (80-98°C) to produce dry powder formulation, then dry powder form is achieved for easier handling and storage, but lipid nanoparticles aggregate and mRNA degrades due to thermal instability

Engineering Contradiction:

Improvedry powder formVSAvoidmRNA integrity

Core Design Contradiction:

ShapeVSStability of the object's composition

Solution Approach 1:

A stabilizing agent is introduced as an intermediary substance between the mRNA-LNP complex and the high-temperature spray-drying environment. This stabilizing agent protects the mRNA from thermal degradation during the spray-drying process while allowing the formation of dry powder particles, thus resolving the contradiction between achieving dry powder form and maintaining mRNA integrity

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The spray-drying process parameters are optimized by controlling temperature profiles, residence time, and atomization conditions to minimize thermal exposure of the mRNA-LNP complex. By carefully adjusting these parameters, the process achieves sufficient drying to form stable dry powder while limiting temperature-induced aggregation and degradation

Inventive Principle:

Principle #35Parameter changes

2Shape

If spray-drying is performed at high temperatures to achieve adequate drying, then dry powder formulation is produced, but lipid nanoparticles melt and aggregate at the spray nozzle

Engineering Contradiction:

Improvedry powder formulationVSAvoidparticle uniformity

Core Design Contradiction:

ShapeVSStrength

Solution Approach 1:

A stabilizing agent serves as a protective intermediary that coats or associates with the lipid nanoparticles during spray-drying. This stabilizing agent prevents lipid melting and aggregation at the spray nozzle by forming a protective barrier or modifying the thermal properties of the nanoparticle surface, enabling uniform particle formation

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The formulation is transformed into a composite system combining mRNA, lipid nanoparticles, and stabilizing agents. This composite structure provides thermal protection to the lipid nanoparticles during spray-drying, preventing aggregation while maintaining the desired dry powder morphology and uniformity

Inventive Principle:

Principle #40Composite materials

3Stability of the object's composition

If lyophilized formulations are used for mRNA, then storage stability is improved, but particle uniformity is unreliable and handling requires dissolution prior to dispensing

Engineering Contradiction:

Improvestorage stabilityVSAvoidhandling convenience

Core Design Contradiction:

Stability of the object's compositionVSEase of operation

Solution Approach 1:

The formulation is transformed from a lyophilized solid to a dry powder with optimized physical properties. By controlling the spray-drying process parameters and formulation composition, the dry powder achieves flowability, freedom from caking, and uniform particle size distribution, making it as easy to handle as conventional dry powders without requiring dissolution

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The dry powder formulation is designed for single-use dispensing similar to conventional dry powder inhalers. Each dose can be directly loaded into a metered dose inhaler and administered without preparation, eliminating the need for dissolution steps required by lyophilized formulations while maintaining storage stability

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

4Stability of the object's composition

If liquid formulations are used for mRNA, then mRNA integrity is maintained, but administration requires invasive methods like injections or nebulizers

Engineering Contradiction:

ImprovemRNA integrityVSAvoidadministration route

Core Design Contradiction:

Stability of the object's compositionVSEase of operation

Solution Approach 1:

The formulation is transformed from liquid phase to dry powder phase through spray-drying. This phase transition enables the mRNA-LNP complex to be delivered via inhalation of dry powder particles, which are then rehydrated in the respiratory tract, providing a non-invasive administration route while maintaining mRNA integrity through the use of stabilizing agents

Inventive Principle:

Principle #36Phase transitions

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 dry powder formulation is stable and maintains high mRNA integrity during long-term storage, allowing for efficient cellular delivery and administration via less invasive routes like metered dose inhalers.

Implementation Method 1

both mRNA and the lipid nanoparticle components are structurally labile at the high temperatures and/or pressures needed for adequate spray-drying... Lipids tend to melt and/or aggregate at the high inlet temperature at or near the spray nozzle... adding a polymer to an mRNA and lipid mixture effectively prevents aggregation of lipid nanoparticles

Methodology Applied

Scientific EffectThermal stabilization:

Implementation Method 2

an inlet temperature of a spray-dryer ranges between 80° C. to 98° C... dry powder (i.e., spray-dried) formulation of mRNA encapsulated with lipid based nanoparticles

Methodology Applied

Scientific EffectSpray-drying: