Optimization of Nasal Drug Delivery from Aerosols to Real-Time Drug Testing on-a-Chip

Research problem A plethora of research has reported the advantageous intranasal delivery of therapeutics for local, systemic, and central nervous system therapies. However, challenges are still remained to improve the efficiency of this drug delivery route given the physiological barriers limiting the drug permeation across the nasal mucosa, i.e. the epithelial barrier function and the rapid mucociliary clearance. Moreover, there is lack of physiologically relevant platforms to conduct nasal drug testing to enhance the predictive power of the preclinical assays. Objectives and aims The major objective of this research is to enhance the efficiency of intranasal drug delivery, which is broken down to two minor objectives as (1) improvement of the nasal drug residence time and mucosal permeation and (2) improvement of relevance of the nasal drug testing platforms. Thereby, the development of a novel thermosensitive nasal formulation capable of transforming into a mucoadhesive gel state upon deposition to the nasal cavity was aimed. The formulation was prepared by chitosan, which offers mucosal permeation enhancing property. In addition, development of a platform for testing the nasal drug delivery under physiologically relevant conditions by mimicking the biological properties and the mechanical stimuli in human nasal mucosa was aimed. This was intended to enhance the predictive power of the preclinical tests conducted to evaluate the efficacy of nasal drugs and hence, facilitate the nasal drug discovery process. To achieve the abovementioned objectives, the following aims were pursued: 1) Review of the research studies on the application of organ-on-a-chip technology in drug testing and the improvements reported in terms of the relevance of the in vitro experiments to the clinical findings as well as the potentials for future studies. 2) Development of a thermosensitive nasal formulation with in situ gel formation capability at the temperature of human nasal cavity for efficient brain targeting through the olfactory nervous system. This was aimed to improve the bioavailability of nasal drugs by enhancing the residence time and permeation of the drugs. 3) Extending the application of the developed nasal formulation for local therapies by studying in vitro nasal wound healing capabilities. This chapter aims to shed insights into how the improved drug bioavailability could enhance the efficacy of drug for localised treatments. 4) Exploring the application of electrochemical technique as an analytical tool to quantify in vitro nasal drug transport. The aim of this chapter is to determine fundamental parameters affecting electrochemical analysis measurements and reliability of the readouts towards developing a new nasal drug testing platform capable of in situ drug quantification as an alternative to the conventional time-consuming and costly analytical approaches. 5) Development of an in vitro microfluidic model for human nasal epithelial mucosa to better mimic the physiological characteristics and dynamic mechanical cues in human nasal mucosa compared to conventional static models. The aim is to enhance the predictive ability of in vitro nasal drug testing platforms by simulating the realistic dynamic microenvironment. This is followed by the integration of reliable analytical tools in the model to facilitate in vitro nasal drug transport quantification by performing in situ measurements. 6) Further improvement on the physiological relevance of the microfluidic nasal epithelium model by emulating the flow and deposition of nasal spray particles on nasal mucosa. This is intended to bring crucial insight into understanding whether the nasal drug delivery is influenced by the mechanical stimuli in human nasal mucosa in vivo.