Design and In Vivo Evaluation of Polymeric Micelles for Improved Oral Delivery of Ritonavir

Abstract

Ritonavir (RTV), an important HIV protease inhibitor, exhibits poor aqueous solubility and limited oral bioavailability, resulting in variable therapeutic performance. The present study aimed to develop and evaluate PEG-PCL-based polymeric micelles to enhance the solubility, dissolution, and oral bioavailability of ritonavir. RTV-loaded polymeric micelles were prepared by the thin-film hydration method and optimized using a 3² factorial design by varying the drug-to-polymer ratio and sonication time. The optimized formulation was characterized for particle size, encapsulation efficiency, and physicochemical properties, followed by in vivo pharmacokinetic evaluation in Sprague-Dawley rats. Pharmacokinetic studies demonstrated that the optimized polymeric micelles significantly enhanced systemic exposure, producing a 4.1-fold increase in peak plasma concentration (C_max) and a 3.8-fold increase in AUC₀–₂₄ compared with the pure ritonavir suspension, corresponding to a relative oral bioavailability of 380%. Histopathological examination of gastric and intestinal tissues revealed no signs of inflammation or mucosal damage, confirming the safety of the developed formulation. The enhanced oral absorption was attributed to improved solubilization, sustained drug release, and increased intestinal permeability provided by the PEG-PCL micellar system. These findings demonstrate that PEG-PCL polymeric micelles represent a promising and safe nanocarrier platform for improving the oral delivery and therapeutic efficacy of poorly water-soluble drugs such as ritonavir.