This study aimed to enhance the antimicrobial properties of daptomycin by ion-pairing with ethyl lauroyl arginate (ELA) and incorporation in a self-emulsifying drug delivery system (SEDDS).Daptomycin was ion-paired with the ELA and the hydrophobic ion pair (HIP) was loaded into SEDDS. SEDDS 1 consisted of 15 % oleic acid, 5 % soy phosphatidylcholine, 10 % cetyltrimethylammonium bromide (CTAB) in medium-chain triglycerides (MCT) at a concentration of 250 mg/ml, 20 % benzyl alcohol, and 50 % PG-4 caprate. SEDDS 2 comprised 10 % soy phosphatidylcholine in MCT at a concentration of 53 mg/ml, 10 % CTAB, 20 % benzyl alcohol, and 60 % PG-4 caprate. SEDDS were characterized regarding droplet size, polydispersity index (PDI), zeta potential, and stability. Cytotoxicity was evaluated on Caco-2, HeLa, and SW620 cells. Antimicrobial activity was assessed by agar diffusion studies and time-kill assays with Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans.Both formulations showed a droplet size below 200 nm with a PDI <0.4, a positive zeta potential, and robust thermodynamic stability. They exhibited low toxicity profiles while maintaining full antimicrobial efficacy on all tested pathogens. Compared to unformulated daptomycin, SEDDS 1 and 2 lowered the minimum inhibitory concentration (MIC) 5- and 8- fold for S. aureus and 10- and 30- fold for S. epidermidis, respectively. Bacterial killing time was 105 -fold shortened with SEDDS 1 and 106 -fold with SEDDS 2. Furthermore, HIP and SEDDS enhanced antibacterial activity against Candida albicans and Pseudomonas aeruginosa. According to these results, ion pairing of daptomycin with ELA and incorporation into SEDDS is a promising approach to improve the antimicrobial activity of this drug.
Read full abstract