In 2020, CDER’s Office of Generic Drugs (OGD) and several partner researchers quantified the effect of drug solubility and partition coefficient on the dissolution and subsequent uptake of drugs in a realistic nasal cavity model. The results provided insight into the possible effects of formulation variables such as solubility, partition coefficient, and particle size on systemic exposure inside the nasal cavity. Complex locally-acting generic drug products, such as some orally inhaled or nasal drug products, can be more challenging for generic drug developers to copy, often leading to a lack of generic competition even after patents and exclusivities no longer block generic drug approval. Accurate and realistic predictions from computer simulations about deposition and absorption of nasally inhaled drugs can provide a deeper understanding of complex fluid-particle dynamics in the nasal cavity which may help OGD clarify regulatory expectations early in the drug development process and during application assessment.
While most nasal drug products target local drug delivery to nasal tissues, there is an interest within industry for developing products that target blood-brain barrier (BBB) for rapid delivery to the central nervous system (Pardeshi et al., 2013). As nasal drug products with BBB targeting enter the market, there will be a need for understanding how to assess bioequivalence for proposed generic versions of these products. Currently available models for predicting drug deposition and absorption of nasal drug products such as the model developed by Rygg et al. (2016) have shown promise but are incapable of accurately predicting local absorption. To facilitate accurate local nasal deposition predictions, a three-dimensional (3D) model using computational fluid dynamics (CFD) was developed for this study that includes a paired mucus layer model.
Determining How to Enhance Drug Uptake through Clearance, Dissolution, and Absorption
The noninvasive nature of intranasal drug administration makes it a widely adopted technique for local and systemic delivery of therapeutic agents. The nasal mucosa, unlike other mucosae, is easily accessible. Intranasal application circumvents the issues of gastrointestinal degradation and hepatic first pass metabolism of the drug (Bitter et al., 2011).
However, drugs intended to hit a target site within the nasal cavity are also trapped in the highly viscous gel layer reducing the efficacy of the drug. Soluble drugs, however, dissolve in the mucus layer, diffuse across the gel and sol layers, and are eventually absorbed by the richly vascularized nasal epithelium. This enables a drug to enter the systemic regions through the blood stream without losing efficacy.
A computational 3D mucociliary clearance (MCC) model was developed for this study, with the goal of realistically quantifying the effects of drug solubility and partition coefficient on the dissolution and subsequent uptake of drugs in the nasal cavity to achieve a desired therapeutic effect. The results of the study provide insight into the effects of formulation variables like solubility and partition coefficient on systemic exposure inside the nasal cavity. The goal is to eventually enhance drug uptake through a combination of clearance, dissolution, and absorption, as well as drug targeting, to maximize drug uptake.
Methods
The open-source CFD flow solver toolbox, OpenFOAM version 1706 , was employed for the development of the computer simulation model. As part of the design, a novel 3D meshing technique allows the model to smoothly capture the relatively large flow domain as well as the micron-size mucus layer. This efficient meshing strategy drastically reduces the overall meshing time from hours to a matter of minutes. Segmental concentration contours as a visualization tool explai...
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