Aerosolised Nanoparticles for Nose-to-Brain Drug Delivery (NTBDD)

: (Alternative Format Thesis)

Abstract

The effective therapy of Central Nervous System (CNS) disorders has been a challenging task. The available treatment options are either systemic with insufficient outcomes or localized but disruptive. The CNS is shielded with the tight Blood Brain Barrier (BBB), the main roadblock, its unique and uninterrupted structure is highly selective to molecule transport into and out of the brain. Intranasal (IN) administration has emerged as a promising approach as a direct and invasive drug delivery route to the brain bypassing the BBB. It is convenient, painless and offers direct and efficient entry for drug/formulation via the BBB-free olfactory neuroepithelium and the olfactory neurons in the nasal cavity. Nevertheless, nasal pathway has its own hurdles such as the limited capacity (≤ 200 µL), enzymatic degradation, mucociliary clearance and the minute deposition in the uppermost olfactory region which counts for only 3-5% of the nasal cavity. To overcome these obstacles a suitable nasal formulation and delivery device are required for ideal Nose-to-Brain Drug Delivery (NTBDD). This work examines the synergistic effect of a nano-formulation and a propellent-driven pressurised metered dose inhaler (pMDI) to improve the olfactory deposition and hence the brain dosing. The diffusive nanoparticles along with the self-contained force device would offer particle transport deeper in the nasal cavity enabling the olfactory targeting.

Two colloidal delivery systems made of PLGA nanoparticles (PLGA NPs) and gold nanoparticles (GNPs) were investigated for their morphological properties. Utilizing a unique aerosol deposition system, particle stability within the pMDI formulation (EtOH + HFA134a propellant) and following aerosolization was screened. The nasal deposition studies were performed under different administration techniques using optimised 3D-printed human nasal replica. And, for the first time an RPMI 2650 cell-based nasal deposition model which combines the morphological as well as the physiological characteristics of human nose was developed to perform parallel deposition, nasal epithelial integrity, and permeation studies for the pMDI-co-PLGA NPs.
The spherical PLGA NPs and the urchin-like GNPs were intact and discrete after atomization with the pMDI device. For 8% and 5.6% olfactory deposition was achieved for PLGA NPs and urchin-GNPs respectively. Both systems had no critical damaging effect on the RPMI 2650 nasal cell model in aerosol form. The novel cell inspired deposition model was successfully employed confirming the integrity of the cellular barrier and a considerable deposition of the PLGA particles in the olfactory region.
Our promising findings are a call for nasally inhaled medicine developers and formulators to follow the pMDI-co-NPs approach as a great potential for NTBDD applications and therefore reducing the gap towards effective treatment for CNS diseases.

Date of Award	29 Mar 2023
Original language	English
Awarding Institution	University of Bath
Supervisor	Paul De Bank (Supervisor), Ian Blagbrough (Supervisor) & Robert Price (Supervisor)