Oral peptide drug delivery: design of SEDDS providing a protective effect against intestinal membrane-bound enzymes

This study presents an emerging approach for oral peptide drug delivery by designing self-emulsifying drug delivery systems (SEDDS) capable of protecting peptide drugs from intestinal brush border membrane-bound (BBM) enzymes. Tuftsin was incorporated as a model peptide into three optimized SEDDS formulations through hydrophobic ion pairing with the anionic surfactants docusate (AOT), N-octadecyl sulfate (OS), and lauryl sulfate (LS). SEDDS- 1 consisted of octyldodecanol, polyoxyethylene (10) oleyl ether, polyoxyethylene (20) oleyl ether and citronellol. SEDDS- 2 were formulated with isopropylmyristate, polyoxyethylene (20) oleyl ether and eugenol. SEDDS- 3 included caprylic acid, PEG- 35 castor oil and citronellol. The resulting nanoemulsions were characterized for droplet size, zeta potential, polydispersity index (PDI), and stability in biorelevant media. Enzymatic degradation studies with aminopeptidase N and ex vivo rat small intestine revealed remarkable protective effects. SEDDS- 3 exhibited superior performance, preserving over 80% of tuftsin after 4 h, followed by SEDDS- 2 protecting 70% of tuftsin, while the unformulated peptide was entirely degraded within 20 min. Furthermore, SEDDS- 2 demonstrated enhanced permeation of tuftsin across intestinal mucosa by achieving a 4-fold increase, while SEDDS- 3 led to a 3-fold enhancement in permeation compared to the unformulated peptide. Accordingly, SEDDS- 3 demonstrates the greatest potential for peptide delivery due to its superior protective performance and enhanced permeation compared to the control. These findings underscore the potential of SEDDS as a versatile platform for safeguarding peptide drugs against enzymatic degradation in the intestinal environment. By modifying their composition, SEDDS can unlock new possibilities for efficient oral peptide drug delivery, overcoming critical enzymatic and mucosal barriers.