In Vitro Anatomical Models for Nasal Drug Delivery

Abstract

Nasal drug delivery has been utilized for locally acting diseases for decades. The nose is also a portal to the systemic circulation and central nervous system (CNS). In the age of SARS-CoV2, the development of nasal sprays for vaccination and prophylaxis of respiratory diseases is increasing. As the number of nasal drug delivery applications continue to grow, the role of targeted regional deposition in the nose has become a factor is nasal drug development. In vitro tools such as nasal casts help facilitate formulation and product development. Nasal deposition has been shown to be linked to pharmacokinetic outcomes. Developing an understanding of the complex nasal anatomy and intersubject variability can lead to a better understanding of where the drug will deposit. Nasal casts, which are replicas of the human nasal cavity, have evolved from models made from cadavers to complex 3D printed replicas. They can be segmented into regions of interest for quantification of deposition and different techniques have been utilized to quantify deposition. Incorporating a nasal cast program into development can help differentiate formulations or physical forms such as nasal powder versus a liquid. Nasal casts can also help develop instructions for patient use to ensure deposition in the target deposition site. However, regardless of the technique used, this in vitro tool should be validated to ensure the results reflect the in vivo situation. In silico, CFD simulation or other new developments may in future, with suitable validation, present additional approaches to current modelling, although the complexity and wide degree of variability in nasal anatomy will remain a challenge. Nonetheless, nasal anatomical models will serve as effective tools for improving the understanding of nasal drug delivery.

In vitro Evaluation of Paliperidone Palmitate Loaded Cubosomes Effective for Nasal-to-Brain Delivery

“…This good result arises from the combination of an appropriate Dv50 and an adapted administration device intended for N2B delivery via the production of a narrow plume angle and a high ejection velocity. These results in the nasal cast are encouraging, given the promising in vivo – in vitro correlation obtained by Williams et al 55 However, an in vivo study remains necessary considering the discrepancies between cell lines and ex vivo permeation studies but also to determine if nasal irritation is low enough given the in vitro cytotoxicity results. Such studies will be the subject of a future paper.…”

“…Indeed, in their work, the majority of the powder was also found in the middle turbinates and the olfactory region in the nasal cast (about 40 and 35% for the middle turbinates and the olfactory region, respectively) and in the in vivo study (about 35 and 38% for the turbinates and the olfactory region, respectively). 55 …”

“…Indeed, although nasal casts are not yet a regulatory test, a recent study by Williams et al validated this model as a suitable in vitro tool to assess in vivo deposition of a nasal product. 55 …”

A Supine Position and Dual-Dose Applications Enhance Spray Dosing to the Posterior Nose: Paving the Way for Mucosal Immunization

“…This study can be further improved if more physiological factors can be considered, including a large cohort of nose models, more delivery scenarios, and compliant walls. Intranasal spray dosimetry is sensitive to nasal anatomical details; the inter-subject variability can be large and warrants future investigations [ 54 , 55 , 56 , 57 ]. It will be desirable to know the range or confidence level of the nasal dosage for a given device, formulation, and targeted patient population (e.g., child, adult, senior) [ 36 , 58 , 59 , 60 ].…”

Comparison of Aerosol Deposition Between a Cynomolgus Macaque and a 3D Printed Cast Model of the Animal

“…Indeed, the thickness of the mucus and mucocilliary clearance condition the deposition and behaviour (rheology characteristics, such as surface tension and viscosity) of deposited particles [ 31 ], especially in the URT. Williams and Suman [ 32 ] also described that the lack of mucosal surface and ciliary clearance constitutes a limitation for nasal anatomical models. The moisture content and temperature in the airways could also modify the particle size, affecting the deposition along the airways [ 33 ].…”