Nano-Enabled Toxicity of Pharmaceutical Excipients.

Nanotechnology has brought revolutionary advances in the pharmaceutical field. Among drug delivery systems, nanocarriers, which enhance the solubility, stability and membrane permeability of numerous drugs, have become indispensable. However, nanocarriers not only amplify the therapeutic potential of drugs but can also increase the toxic potential of excipients used in their formulation. For example, commonly used excipients such as polyethylene glycol, cationic polymers (e.g., polyethylenimine), cationic lipids, metal-based materials, and cyclodextrins may exhibit altered, and often enhanced, toxicological profiles when formulated as nanocarriers. This so-called nano-enabled toxicity of pharmaceutical excipients is frequently overlooked, as excipients with a pharmacopoeial monograph are generally considered safe. However, many of these excipients were approved before the widespread use of nanocarriers, and their safety with respect to nano-enabled toxicity has therefore not been systematically evaluated. Regulatory frameworks are still evolving and only partially address these risks. It is therefore the aim of this review to highlight the nano-enabled toxicity of pharmaceutical excipients, propose methods to assess these additional safety risks during early-stage development, and discuss approaches to replace problematic excipients with safer alternatives.