Nanotechnology-Driven Bioavailability Enhancement: A Critical Review of BCS Class II and IV Drugs

Abstract

One of the major hurdles for the oral drug development is poor aqueous solubility. BCS Class II drugs are low solubility and relatively high permeability drugs and Class IV drugs are low solubility and low permeability drugs. Their absorption can thus be limited by dissolution, luminal solubilization, epithelial transport, efflux, metabolism and first pass extraction. Nanotechnology provides a variety of formulation strategies including nanocrystals, nanosuspensions, solid lipid nanoparticles, nanostructured lipid carriers, self-nanoemulsifying systems, nanoemulsions and polymeric or hybrid nanoparticles. We present in this review a mechanism-first framework connecting drug liabilities with gastrointestinal fate and nanocarrier selection. It addresses dissolution enhancement, mucus and unstirred-water-layer transport, epithelial uptake, P-glycoprotein/CYP-mediated presystemic loss and lymphatic transport. Particular attention is paid to formulation development, Quality by Design, biorelevant dissolution and lipolysis, critical quality attributes, scale-up, stability, safety, advanced intestinal models, pharmacokinetic predictability and regulatory translation. The review argues that the most useful oral nanomedicines are not just smaller particles but reproducible systems designed to overcome a defined absorption bottleneck while remaining scalable, stable, safe and clinically interpretable.