Atorvastatin-loaded frankincense self-nanoemulsifying drug delivery system (SNEDDS) thermoresponsive hydrogel enhances wound healing in an animal model

Abstract

Atorvastatin (ATR) is a well-established antihyperlipidemic agent that has recently gained attention in wound-healing research for its pleiotropic anti-inflammatory and antioxidant properties. Despite this therapeutic potential, its clinical repurposing for topical application remains challenging because of its poor aqueous solubility (BCS Class II) and limited penetration across the skin barrier. To address these limitations, ATR was incorporated into a self-nanoemulsifying drug delivery system (SNEDDS), which possesses inherent wound-healing properties, and subsequently incorporated into a thermoresponsive hydrogel to develop a novel ATR-SNEDDS hydrogel aimed at enhancing wound-healing efficacy. ATR-SNEDDS formulations were prepared using frankincense) FRK (oil, Tween® 20, and PEG 400 and characterized for thermodynamic stability, emulsification efficiency, droplet size, cloud point, and drug content. The optimized formulation, exhibiting nanometric droplet size, high drug content, and excellent physical stability, was then incorporated into a thermosensitive poloxamer hydrogel using the cold method, which demonstrated improved spreadability, suitable rheological properties, and complete drug release within 6 h. In a rat incisional wound model, the ATR-SNEDDS hydrogel significantly enhanced wound contraction (40% vs. diseased group; 16% vs. marketed standard), accompanied by marked reductions in oxidative stress and inflammatory markers, including malondialdehyde (68%) and TNF-α (60%), along with increased antioxidant defenses as evidenced by elevated SOD (48%) and GSH (50%). Histopathological and immunohistochemical analyses confirmed accelerated re-epithelialization, enhanced collagen deposition, and reduced inflammatory infiltration. Collectively, these findings demonstrate that the ATR-SNEDDS thermosensitive hydrogel provides a synergistic and effective platform for improving the therapeutic performance of ATR, offering promising wound-healing potential in an acute incisional wound model.