Formulation Optimization and in Vitro–in Vivo Evaluation of Alpha Lipoic Acid-Loaded Lipid–Polymer Hybrid Nanoparticles Via Design of Experiments

Abstract

Purpose

Alpha lipoic acid (ALA) is a natural compound that has recently gained attention for its anti-inflammatory potential. ALA has a low bioavailability and in vitro stability, making its clinical use a challenge. Lipid–polymer hybrid nanoparticles (LPHNPs), a newly discovered core-shell nanostructures, are derived from liposomes and polymeric nanoparticles, and they were commonly used to improve in vivo efficiency and stability of active substances.

Methods

The current study aimed to prepare ALA-loaded LPHNPs via the design of experiments (DoE) approach to improve oral bioavailability and in vitro stability of ALA. The Plackett-Burman design was used to select independent variables by evaluating the effects of drug amount, stirring rate, polymer amount, lipid/polymer ratio, water/organic solvent (W/Os) ratio, and polyvinyl alcohol (PVA) concentration on formulation properties. Afterward, statistically significant formulation parameters were optimized using the Box-Behnken design (BBD). Finally, the in vitro properties were evaluated, and the in vivo anti-inflammatory effect of the optimized formulation was tested using formalin-induced paw edema in mice.

Results

The main factors affecting the mean particle size (mPS), polydispersity index (PdI), and ζ potential (ZP) values of ALA-loaded LPHNPs were the stirring rate, W/Os ratio, and PVA concentration; however, the independent variables had no significant effect on encapsulation efficiency (EE). Furthermore, optimized ALA-loaded LPHNPs also significantly reduced paw edema thickness and volume with a prolonged duration of action compared to ALA solution during 6 h after formalin administration.

Conclusion

The optimized ALA-loaded LPHNPs with core-shell structure had sustained control release up to day 17 and exhibited superior colloidal and chemical stability under various in vitro conditions and prolonged and robust in vivo anti-inflammatory effect.

Graphical Abstract