Mireia Puig-Sellart, Carla B. Roces, Anand Bakle & Gemma Keegan
Phillips Medisize UK, 1-6, Prospect West, Bumpers Way, Chippenham SN14 6FH, United Kingdom
Summary
Delivering oligonucleotide therapies to the lungs holds promise for treating various conditions, especially using mRNA in lipid nanoparticles (LNPs). These mRNA-LNP liquid systems are adaptable for vaccines and protein replacement therapies but are hindered by cold chain storage. Particle engineering offers a solution by enabling the production of inhalable dry powders, potentially reducing cold chain dependency. However, this process can destabilize LNPs, particularly through colloidal instability by nanoparticle aggregation. This study explored a surrogate LNP system containing polyadenylic acid (poly(A)), spray dried with trehalose (Tre) and either crystalline leucine (Leu) or amorphous trileucine (LLL) as shell-forming agents. It was hypothesized that poly(A)-LNPs interact with crystalline Leu at the particle surface, leading to aggregation and increased particle size (>500 nm). In contrast, LNPs spray dried with LLL retained colloidal stability, maintaining particle sizes below 155 nm. Shell-forming agents significantly improved aerosol performance. Dose escalation using the O1 device (a novel proprietary unit dose dry powder inhaler platform for high formulation payloads) was demonstrated and delivered up to 51 µg of equivalent lung dose to the lungs. In conclusion, poly(A)-LNP powders formulated with LLL outperformed those with Leu or no shell former, offering superior colloidal stability and aerosol delivery with the O1 device.
Snezana.Puig-Sellart