Characterization of a custom 3D-printed microfluidic aerosolizer for enhanced nose-to-brain delivery of nanoemulsion

Abstract

Nose to brain (N2B) delivery offers a potential means of bypassing challenges associated with drug delivery across the blood brain barrier. The goal of this study was to evaluate the in vivo efficacy of a rat-sized, 3D-printed nasal aerosol delivery system.

Highlights

Preclinical aerosolized intranasal delivery in animals can improve drug translation.
A 3D-printed aerosolizer was used for the nasal delivery of nanoformulations.
Aerosolizer geometry and solution properties interact to influence droplet size.
Nanoemulsion formulation properties can improve nasal cavity retention.
Both device aerosolization and formulation are necessary to study nasal delivery.

Aerosolizer design and delivery parameters were assessed for their impact on aerosol droplet size. Additionally, the impact of nanoemulsion vehicle formulation on fluorophore retention and nasal tissue penetration was evaluated. Intranasal administration was conducted using a 3D-printed aerosolizer. Geometric parameters of the aerosolizer were systematically varied, and phase contrast microscopy was used to evaluate aerosol droplet size. Aerosolization with NeutrAvidin™-labeled FluoSpheres™ in various nanoemulsion formulations was performed in 17 anesthetized adult Sprague Dawley rats. The rats were sacrificed 30 min later, and the nasal mucosa was prepared for viewing under a laser-scanning confocal microscope. Z-stack reconstructions were performed to assess the depth of fluorophore penetration.

The aerosolizer produced average droplet diameters between 5–7 µm. Shorter nozzle length, increased actuation pressure, increased delivery distance, and removal of reservoir dead space significantly reduced mean aerosol droplet size when delivering nanoparticles dispersed in saline. Compared to the delivery of a saline control solution, the delivery of NeutrAvidin™-labeled FluoSpheres™ in a nanoemulsion vehicle containing 8 % Peceol™, 2 % Gelucire® 59/14, and 0.5 % Labrafac® MC60 in deionized water resulted in a significantly higher proportion of screened nasal cavity sections containing fluorescence. A custom-designed 3D-printed aerosolizer delivered a nanoemulsion preparation specifically to the posterior nasal cavity of rats—a region that is particularly relevant for targeting the olfactory epithelium to enhance N2B delivery.