A Computational Systems Approach to Rational Design of Nose-to-Brain Delivery of Biopharmaceutics

In this work, a computational systems approach, comprising models at different time and length scales, is developed to elucidate the fundamental chemical, physical, transport, and biological processes in relation to the design of a novel nose-to-brain drug delivery system for the treatment of neurodegenerative diseases. In particular, a kinetic model is established to describe the formation of a hydrogel patch, via the enzymatic cross-linking of tyramine-modified hyaluronic acid, on the olfactory cleft. A fluid transport model is employed to describe the flow of a cross-linkable viscoelastic polymer solution through an applicator in terms of tube and reactive fluid characteristics (e.g., tube geometry, volumetric flow rate, and viscosity). The spreading of the deposited HA droplet on a mucus substrate is modeled via the development of a dynamic droplet deformation model. Subsequently, a dynamic drug release model is formulated to quantify the release rate of an active pharmaceutical ingredient (e.g., long-acting insulin analogues) from a distributed population of drug-loaded polymeric carriers embedded into a hydrogel matrix in terms of molecular and morphological properties of the hydrogel drug carriers system. Finally, the drug flux from the hydrogel mucosa interface to the olfactory bulb via the epithelium and lamina propria olfactory sublayers is modeled with a series of dynamic mass transport models. The various mathematical models are integrated together following a multiscale modeling approach to aid the identification of key design system parameters and material properties that can lead to the optimization of the complex drug carriers hydrogel, droplet deposition, film formation, and drug delivery system to achieve a desired therapeutic effect over a two-week delivery time.