The Optimization Design Of Lactoferrin Loaded HupA Nanoemulsion For Targeted Drug Transport Via Intranasal Route

Int J Nanomedicine. 2019 Nov 27:14:9217-9234. doi: 10.2147/IJN.S214657. eCollection 2019.

Abstract

Background: Huperzine A (HupA) is a selective acetylcholinesterase inhibitor used to treat Alzheimer's disease. The existing dosage of HupA lacks brain selectivity and can cause serious side effects in the gastrointestinal and peripheral cholinergic systems.

Purpose: The aim of this study was to develop and characterize a HupA nanoemulsion (NE) and a targeted HupA-NE modified with lactoferrin (Lf) for intranasal administration.

Methods: The NE was formulated using pseudo-ternary phase diagrams and optimized with response surface methodology. Particle size distribution and zeta potential were evaluated, and transmission electron microscopy was performed. We investigated the transport mechanisms of HupA-NEs into hCMEC/D3 cells, an in vitro model of the blood-brain barrier. HupA-NE, Lf-HupA-NE, and HupA solution were intranasally administered to rats to investigate the brain-targeting effects of these formulations. A drug targeting index (DTI) was calculated to determine brain-targeting efficiency.

Results: Optimized HupA-NE had a particle size of 15.24±0.67 nm, polydispersity index (PDI) of 0.128±0.025, and zeta potential of -4.48±0.97 mV. The composition of the optimized HupA-NE was 3.00% isopropyl myristate (IPM), 3.81% Capryol 90, and 40% Cremophor EL + Labrasol. NEs, particularly Lf-HupA-NE, were taken up into hCMEC/D3 cells to a greater extent than pure drug alone. Western blot analysis showed that hCMEC/D3 cells contained P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance associated protein 1 (MRP1) transporters. The likely mechanisms resulting in higher NE transport to the brain were uptake by specific transporters and transcytosis. In vivo, intranasal Lf-HupA-NE significantly enhanced drug delivery to the brain compared to HupA-NE, which was confirmed by differences in pharmacokinetic parameters. The DTI of Lf-HupA-NE (3.2±0.75) demonstrated brain targeting, and the area under the curve for Lf-HupA-NE was significantly higher than that for HupA-NE.

Conclusion: Lf-HupA-NE is a promising nasal drug delivery carrier for facilitating delivery of HupA to the central nervous system.

Keywords: brain targeting; intranasal delivery; lactoferrin; nanoemulsion.

MeSH terms

  • Administration, Intranasal
  • Alkaloids / pharmacokinetics
  • Alzheimer Disease / metabolism
  • Animals
  • Biological Transport
  • Blood-Brain Barrier / metabolism
  • Brain / drug effects
  • Cell Line
  • Drug Liberation
  • Emulsions / chemistry*
  • Humans
  • Lactoferrin / administration & dosage
  • Lactoferrin / chemistry*
  • Male
  • Nanoparticles / administration & dosage
  • Nanoparticles / chemistry*
  • Nasal Mucosa / metabolism
  • Particle Size
  • Phase Transition
  • Rats, Wistar
  • Sesquiterpenes / pharmacokinetics
  • Solubility
  • Static Electricity
  • Tissue Distribution

Substances

  • Alkaloids
  • Emulsions
  • Sesquiterpenes
  • huperzine A
  • Lactoferrin