Background: The oral delivery of biopharmaceuticals remains a major challenge for researchers and the pharmaceutical industry. Therefore, extensive research is ongoing to develop a viable delivery method, hence self-emulsifying drug delivery systems (SEDDSs) are being investigated because of their ability to protect the carried macromolecules in the gastrointestinal environment and facilitate absorption through the intestinal barrier. Objectives: To systematically investigate this promising method for the oral delivery of lysozyme (LYZ) and to model oral peptide/protein administration. Methods: LYZ/sodium dodecyl sulfate (SDS) hydrophobic ion pairs (HIPs) were prepared to enhance protein solubility and stability in SEDDSs. Different surfactants (Tween^® 20 and 80) and as co-surfactants (Span^® 20 and 80) were combined for the preparation of liquid SEDDSs according to a 2² full factorial design and samples of each combination were formulated based on a three-factor-constrained mixture design. The critical quality attributes (CQAs), droplet size, polydispersity index (PDI), and zeta potential were measured by dynamic light scattering (DLS). The process design space was determined by response surface methodology (RSM) and two-dimensional ternary contour plots. An in vitro release test was performed using the sample-and-separate approach. Results: Emulsions of SEDDSs with the optimal properties of droplet size < 200 nm, PDI < 0.4 and zeta potential < −10 mV were prepared. Consequently, a HIP load of 10 mg/g was achievable, exhibiting apparent first-order kinetics, with approximately 80% of the loaded LYZ released within 6 h. Conclusions: This study may contribute to better understanding of the effects and interactions of formulating materials for SEDDSs and their possible role in the oral delivery of biopharmaceuticals.

Background: Oral protein delivery is a major challenge in the field of pharmaceutical technology due to poor stability and limited permeability through intestinal barriers. Buccal delivery is a promising alternative with less restricting physiological conditions; however, low protein permeability is still a limiting factor. Multiple nanocarriers have been proposed to improve buccal protein delivery with lipid–polymer hybrid nanoparticles (LPHNs) combining the advantages of both polymeric and lipid-based systems. However, these conventional carriers rely on passive protein protection and lack adaptive release mechanisms. Objectives: This work aimed to develop and systematically optimize an ionic strength-responsive LPHN system that can minimize protein release in buccal ionic conditions while offering a triggered release in plasma after absorption. Methods: LPHNs were prepared by a two-step approach where polymeric cores of Eudragit-L100 were prepared by electrostatic complexation with Lysozyme (LYZ) followed by lipid shell formation by the ethanol injection method. Systematic optimization was performed using two-level factorial and central composite designs. Moreover, the ionic strength responsiveness and in vitro LYZ release were investigated in different ionic strength media. Results: The final optimized formulations, LPHNs and sodium deoxycholate-containing LPHNs (NaDC-LPHNs), exhibited a particle size of 257.2 ± 1.5 nm and 246 ± 5.7 nm, encapsulation efficiency of 69.89 ± 0.22% and 68.14 ± 0.16%, and high drug loading efficiency of 24.11 ± 0.06% and 23.65 ± 0.04%, respectively. Moreover, both formulations showed minimal protein release at low ionic strength (buccal-like) conditions while demonstrating a triggered release at higher ionic strength (plasma-like) conditions. Conclusions: The developed system may provide a promising smart strategy to improve buccal protein delivery by enhancing buccal protection and improving systemic delivery.