Development of stable liquid formulations for oligonucleotides.

Area of Science:

• Biotechnology and Pharmaceutical Sciences
• Nucleic Acid Chemistry
• Drug Delivery Systems

Background:

• Oligonucleotide therapeutics represent a promising new class of drugs.
• Developing stable parenteral formulations is crucial for their clinical application.
• Understanding formulation effects on modified oligonucleotides is essential for drug development.

Purpose of the Study:

• To investigate the stabilizing and de-stabilizing effects of formulation parameters on LNA SSOs.
• To identify optimal conditions for liquid formulations of unconjugated and GalNAc-conjugated LNA SSOs.
• To determine feasible concentrations and terminal sterilization methods for LNA SSO formulations.

Main Methods:

• Evaluation of various buffer systems, pH levels, and excipients.
• Assessment of LNA SSO stability under different temperature, mechanical, and oxidative stress conditions.
• Determination of maximum feasible concentrations for handling and processing.
• Evaluation of terminal sterilization options.

Main Results:

• LNA SSOs exhibited maximum stability under slightly alkaline conditions (pH ~8).
• Spermine and lysine effectively reduced formulation viscosity.
• Heat treatment and gamma irradiation led to significant LNA SSO degradation.
• Optimal formulation parameters were identified for enhanced LNA SSO stability.

Conclusions:

• Formulation optimization is critical for the stability of LNA SSOs.
• Slightly alkaline conditions and specific excipients are key for stable liquid formulations.
• Avoiding heat and gamma irradiation is necessary to prevent degradation during terminal sterilization.