pH-regulated supersaturation enables nanonization of three model drugs for enhanced oral and transdermal delivery

Weakly ionizable drugs constitute the majority of clinically used small-molecule therapeutics; however, their pH-dependent solubility and permeability frequently result in poor bioavailability and suboptimal therapeutic efficacy. Herein, we developed a pH-regulated nanonization strategy that exploits the pKa-dependent solubility characteristics of weak electrolytes to generate drug nanoparticles through controlled supersaturation and polymer-assisted stabilization. Three representative weakly ionizable drugs with distinct ionization properties were selected as model compounds, including albendazole (ABZ, weak base), azelaic acid (AZA, weak acid), and hemin (amphoteric compound). The apparent solubilities of resulting nanoparticles (ABZNPs, AZANPs, and HNPs) increased by approximately 317-fold, 106-fold, and 1,100-fold, respectively, as compared to the corresponding free drugs. ABZNPs displayed excellent stability under simulated gastrointestinal conditions and significantly enhanced oral absorption in rats, yielding a 3.5-fold increase in Cmax and a relative bioavailability of 331.4% compared with a commercial formulation. Meanwhile, AZANPs markedly improved transdermal delivery, achieving 3.3-fold higher skin permeation and over twofold greater skin retention than the raw drug formulation. In a Cutibacterium acnes-induced acne model, a 5% AZANPs ointment achieved therapeutic efficacy comparable to that of a commercial 10% azelaic acid product while reducing local irritation. Mechanistically, AZANPs promoted PPAR-γ activation, suppressed inflammatory cytokine production, normalized epidermal hyperproliferation, and facilitated collagen remodeling. Collectively, In this study, we developed a pH-Regulated nanonization method and validated its feasibility using three model drugs, while acknowledging that its broader applicability warrants further investigation.