Biopharmaceutical Challenges Delivery of Oligonucleotides

Until recently, nonparenteral routes have failed to deliver sufficient quantities of ASO to be systemically therapeutic. The recent advent of novel oral delivery technologies, coupled with the increased tissue residence time for second-generation ASOs, allows oral delivery to achieve therapeutic levels for select systemic indications. This chapter will initially outline certain more conventional aspects of parenteral dosage forms, and then focus on formulation technologies that more specifically address local treatment. For the oral route, we will pass to the biopharmaceutic considerations for both local delivery to the gut and systemic delivery via absorption from solid dosage forms. Incumbent with the discussion on formulations is the need initially to overview the physico-chemical properties of ASOs, which in large part determine their biopharmaceutic characteristics. 

ASOs are synthesized as complex mixtures of diastereomers. In the solid state, they are amorphous, electrostatic, hygroscopic solids with low-bulk densities, possessing very high surface areas, and poorly defined or no melting points. Their good chemical stability allows them to be stored as lyophilized or spray-dried powders, or as concentrated, sterile solutions. For example, the 21-mer ASO Vitrave-ne (fomivirsen sodium intravitreal injectable) is approved in the USA for a storage condition from 2 to 25 °C [2]. 

Due to their polyanionic nature, ASOs are extremely water-soluble under neutral and basic conditions. Consequently, dmg-product concentrations are often only limited by an increase in solution viscosity at very high concentrations (e.g. 300 mg/mL) [3]. Not surprisingly, extremes of pH and ionic strength influence the apparent solubility. In acidic environments such as the stomach, inter-nucleotide linkages are partially neutralized by protonation. With this consequent decrease in their polyanionic status there is a marked decrease in oligonucleotide solubility, an event that can be easily reversed by raising the pH. 

All of the physical-chemical characteristics discussed here are important when designing viable, efficacious formulations with acceptable storage and in-vivo stability. 

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Biopharmaceutical Challenges Delivery of Oligonucleotides 10.3.2.2 Oral Dosing... 

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