Pharmaceutical Considerations and Metabolic Fate of Parenteral Lipid Nanoparticle Dosage Forms.

ABSTRACT

The physical stability of parenteral dispersions for delivery of drugs to patients is of particular clinical importance, given their general overall superior bioavailability compared to other routes of administration. Although official pharmacopeial methods for lipid injectable emulsions have been established for triglyceride oil-in-water dispersions (i.e., "mini-emulsions") through USP Chapter <729>, no pharmaceopeial guidance exists for lipid nanoparticle (LNP)-based "micro-emulsions". At present, there are several LNP-based drugs approved for clinical use, including mRNA vaccines. Moreover, the increased interest in using mRNA as a platform technology for an array of potential therapeutic drug candidates increases the importance of developing appropriate methods to ensure their physical stability, safety and efficacy. For all dispersions and by various detection mechanisms (e.g., electrical, mechanical, mathematical), the fusion or growth of droplets/particles in the large-diameter tails of the particle size distribution (PSD) signals the onset of instability. Consequently, the measurement for LNP dispersions will require the use of a modified optical detection design in order to extend the lower particle detection limit into the "relative" large-diameter tail of the PSD for both light extinction and light-scattering methods based on single-particle optical sensing techniques. Fortunately, the technology is currently available and capable of providing the requisite quantitative analysis.