Development and Optimization of Ionic Strength-Responsive Lipid-Polymer Hybrid Nanoparticles for Buccal Protein Delivery

  • Pharmaceutics. 2026 Jun 11;18(6):719. doi: 10.3390/pharmaceutics18060719.
Eslam Ramadan  1  2 ,  Nooh Mdrmah  3 ,  Martin Deák  1 ,  Norbert Varga  4  5 ,  Edit Csapó  4  5 ,  Tamás Sovány  1 ,  Katalin Kristó  1
Affiliations
  • 1. Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary.
  • 2. Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • 3. Graduate School of Health and Drug Sciences, University of Paris-Saclay, 17, Avenue des Sciences, 91400 Orsay, France.
  • 4. Interdisciplinary Excellence Center, Department of Physical Chemistry and Materials Science, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary.
  • 5. MTA-SZTE Lendület "Momentum" Noble Metal Nanostructures Research Group, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary.
PMID: 42357335 DOI: 10.3390/pharmaceutics18060719
Abstract

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.

Keywords
LPHN; buccal; ethanol injection; ionic strength; protein delivery; stimuli-responsive.
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