Polysaccharide-peptide complexes stabilized around nanoemulsion droplets: A new approach for nasal delivering of pramlintide and insulin

Abstract

Insulin (HIns) and pramlintide (Pram) are peptide drugs currently used to modulate blood glucose concentrations in diabetic patients. Glucose metabolism impairment has also been described to occur in the brain of diabetic and non-diabetic Alzheimer's patients. In this context, restoring the brain glucose balance by HIns and Pram administration has been proposed as a therapeutic approach for Alzheimer's disease treatment. However, despite their potential application in therapeutics, clinical use of these peptides has some drawbacks as their metabolic instability via protease degradation and undesirable pharmacokinetic properties, besides being delivered by invasive and inconvenient administration routes. Considering the above mentioned, in this study, we describe the development of Pram and HIns polyelectrolyte complexes stabilized around nanoemulsion droplets as a new approach to delivering these peptides by nasal route. Firstly, dextran sulfate/Pram (PECDexS/Pram) and chitosan/HIns (PECChi/HIns) polyelectrolyte complexes were prepared and characterized according to their physicochemical properties. Polyelectrolyte complexes-coated nanoemulsions (NE-PECDexS/Pram and NE-PECChi/HIns) were then obtained and characterized according to size, zeta potential, morphology, drug recovery, and association efficiency. Both NE-PECDexS/Pram and NE-PECChi/HIns showed desirable nanotechnological properties before and after incubation in a simulated nasal fluid pH 5.5 at 37 °C and during 30-day storage at 8 °C. Negatively charged NE-PECDexS/Pram showed improved mucodiffusion properties and led to a more sustained permeation profile of Pram across the nasal epithelium. On the contrary, the positively charged NE-PECChi/HIns led to a faster mucosal permeation of HInS compared to the free peptide. These results could support future in vivo studies concerning the potential use of these new drug delivery systems for treating metabolic brain disorders by the nasal route.