Efavirenz-loaded polymeric micelles for pediatric anti-HIV pharmacotherapy with significantly higher oral bioavailability

Abstract

Children constitute the most challenging population in anti-HIV/AIDS pharmacotherapy. Efavirenz (EFV; aqueous solubility 4 µg/ml, bioavailability 40–45%) is a first-line agent in the pediatric therapeutic cocktail. The liquid formulation of EFV is not available worldwide, preventing appropriate dose adjustment and more convenient administration. The bioavailability of liquid EFV is lower than that of the solid formulation. Improving the bioavailability of the drug would reduce the cost of treatment and enable less affluent patients to access this drug. Aim: To encapsulate EFV in polymeric micelles to improve the aqueous solubility and the the oral bioavailability of the drug. Methods: EFV was incorporated into the core of linear and branched poly(ethylene oxide)–poly(propylene oxide) block copolymer micelles. The size and size distribution of the drug-loaded aggregates were characterized by dynamic light scattering and the morphology by transmission electron microscopy. The bioavailability of the EFV-loaded micellar system (20 mg/ml) was assessed in male Wistar rats (40 mg/kg) and compared to that of a suspension prepared with the content of EFV capsules in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in a medium-chain triglyceride (Miglyol® 812). Results: This work demonstrates that the encapsulation of EFV, which is poorly water soluble, into polymeric micelles of different poly(ethylene oxide)–poly(propylene oxide) block copolymers significantly improves the oral bioavailability of the drug, and reduces the interindividual variability. Conclusion: This strategy appears a very promising one towards the development of a liquid aqueous EFV formulation for the improved pediatric HIV pharmacotherapy.