Bilosomal delivery of thymol-glycyrrhetinic acid: a multifaceted strategy to combat multidrug-resistant wound infections

Abstract Purpose Antimicrobial-resistant bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA), have a long-term negative impact on wound healing. To combat the rising problem of bacterial resistance to conventional antibiotics, several antimicrobial nanoparticles have been developed. This study aimed to formulate lipid-based bilosomes loaded with two plant-derived antimicrobial drugs; thymol (Thy) and Glycyrrhetinic acid (GA). Methods The synergistic efficiency of both drugs in healing MRSA-infected skin wounds was characterized in-vitro, ex-vivo, and in-vivo. A factorial experimental design was generated to investigate the effects of surfactant-to-cholesterol ratio, and the amount of bile salt on particle size and polydispersity index. Results The optimized bilosomal formulation containing the least amount of bile salt and span 20 showed small particle size (209.4 nm), and high entrapment efficiency (81.2% and 90 % for GA and Thy, respectively). An early burst release effect was found, essential for providing a rapid therapeutic response at the lowest effective dose. This was followed by a controlled drug release over 24 h. In ex-vivo rat skin, GA and Thy-loaded bilosomal gel showed the maximum skin deposition (65.2% and 71.68%, respectively). The combination of GA/Thy-loaded bilosomes caused a significant increase in killing MRSA. In-vivo efficacy on MRSA-infected wound excision mice model gave similar results where GA/Thy loaded bilosmes caused the most significant decrease in bacterial count and best wound healing results. Conclusion Bilosomes are potential lipid-based nanosystems for topical GA and Thy delivery due to their high skin penetration, antibacterial, and wound healing properties in the treatment of multidrug-resistant wound infections.