The use of alkalizers in sodium caprate-based tablets for oligonucleotide oral delivery

The oral delivery of biologics such as oligonucleotides may be enabled by the use of a chemical permeation enhancer such as sodium caprate (C10). However, C10 has low solubility under acidic gastric conditions which, often combined with poor drug stability, limits absorption when formulated in oral formulations. In this work, we investigated the use of alkalizers in immediate release C10-based formulations to enable the delivery of an oligonucleotide drug, RO7062931. Across the physiological pH range, C10 demonstrated low solubility and RO7062931 demonstrated poor chemical stability at pH values lower than 5, which together present significant obstacles to the oral delivery of the oligonucleotide. Screening alkalizers revealed that these pH-modifying components rapidly raised both the simulated gastric fluid bulk pH and microenvironmental pH when combined with C10, increasing the amount of C10 dissolving. Incorporating the most promising alkalizer, sodium carbonate, into C10-containing tablets of RO7062931 led to improved oligonucleotide chemical stability and C10 solubility under gastric conditions during in vitro testing, with the most effective formulation exhibiting complete RO7062931 stability and full C10 release. Alkalizer addition further contributed to oligonucleotide/C10 co-release, which is important for maximizing permeation enhancement activity at epithelial barriers. These findings offer insight into alkalizer incorporation as a promising strategy to improve the gastric delivery of oral formulations of oligonucleotide drugs and permeation enhancers.