Description
The nasal mucosa offers an effective target for inhaled drugs that either treat localized nasal conditions or quickly deliver drugs to the systemic circulation [1–3]. While nasal spray drug product designs can vary considerably between innovators, most sprays are formulated as either a homogeneous solution or a heterogeneous suspension; in the latter case, solid drug particles are dispersed within a carrier liquid [4]. Despite the many advancements in nasal drug delivery, effectively administering drugs via this route still poses many challenges. One of the main challenges relates to mucociliary motion, which tends to transport and clear drug particles from the nasal cavity after deposition, limiting the available time for drug absorption at the intended site of action [5-8].Many previous nasal spray models have considered solution formulations, where the active drug is already dissolved into a carrier liquid [9-11]. These computational fluid dynamics (CFD) models of nasal spray transport are currently well-developed and show good agreement with in vitro depositional data, but stop at the point of droplet deposition [12-19]. When considering a suspension-type formulation, an accurate model requires simulations of spray droplet transport along with the dissolution of the suspended drug particles in the nasal mucus, during which time mucociliary clearance is occurring. In cases where inhaled particles are either very large or insoluble in mucus, insufficient dissolution may result in reduced drug delivery to the nasal epithelium, reducing the overall effectiveness of the drug product [1,2,20,21]. A recently developed model demonstrates the effects of mucociliary clearance on drug absorption from a suspension formulation [22]. However, this model only considered a flattened surface representation of the nasal cavity, and was therefore unable to show uptake in specific nasal regions (e.g., the olfactory region). To study targeted nasal therapies, it is desirable to model drug uptake in an anatomically-realistic, three-dimensional model.Finally, the effects of interindividual variability on nasal drug delivery and clearance have not been fully quantified. Studies have shown that differences in individual nasal geometry can have a large impact on airflow patterns [26], but the full extent of mucus properties, impaired mucociliary function, or general inflammatory disease states on drug delivery have not been completely explored. Because many nasal spray drug products are used to treat medical conditions that cause variations from a "healthy" state, it is important to quantify how these various factors may influence the overall efficacy of nasal sprays.ObjectivesThe objective is to study the three-dimensional effects of mucociliary clearance on localized drug absorption in respiratory airways, particularly the nasal cavity, utilizing a computational modeling approach. The model should be adaptable to cases of intersubject variability, which may include variations in mucociliary clearance rates, changes in nasal geometry, and the presence of relevant disease states (e.g., nasal inflammation, changes in mucus properties, etc.). The desired outcome is a computational methodology that predicts regional absorption of inhaled drugs, particularly those whose formulations include solid or suspended drug particles and may target specific nasal regions.Detailed DescriptionA computational modeling approach will be developed to study the effects of nasal mucociliary clearance on inhaled drug absorption and the changes that result from differences in drug formulation, disease states, and interindividual anatomical differences. The model should consider realistic three-dimensional nasal airway geometries and account for device effects, inhalation, particle/droplet deposition, and, importantly, drug dissolution and absorption at the epithelium. The approach should provide a direct interface between the mucociliary clearance model and CFD simulations of spray deposition.The physiological model should consider the entire nasal airway from the nostril to the throat; variations to the geometry, representative of interindividual differences, should also be considered. The mucociliary clearance model should be general enough to allow for changes in mucus properties and clearance rates based on healthy and disease states.A straight-forward approach would utilize CFD simulations of inhalation and spray/particle transport to provide regional deposition data, while the three-dimensional mucociliary clearance model would demonstrate localized drug absorption and indicate the efficacy of drug products that target specific nasal regions. Since the development of the methodology for creating the three-dimensional CFD mucociliary clearance model is considered a primary outcome of this research, it is expected that the methodology would be made available to the FDA and preferably to the public as well in such a way that it may be reproduced, either through detailed publication of the methodology and/or through sharing of codes, models, etc. Validation of the CFD simulations with in vitro or in vivo data should be included, which should demonstrate similarity between predicted local mucociliary clearance and in vivo clearance of drug particles. If possible, it is preferable that the model be validated against multiple drug products. All relevant physics should be considered in the model; these physics may include (but are not limited to) spray turbulence, Lagrangian droplet/particle transport, mucus properties, mucociliary clearance, particle dissolution, and drug partitioning between the mucus and nasal epithelium. The proposal can include specific drug products to be studied; however, after award, the selection of drug products will be revisited in a collaborative discussion with the FDA. Suspension formulations or insufflation studies would be encouraged.The study should consist of four phases:Phase 1: Selection, identification, and construction of physiological models and inhalation patterns that will best characterize interindividual variability.Phase 2: Development and validation of the computational fluid dynamics model and mucociliary clearance model.Phase 3: Performance of simulations and post-processing of simulation data.Phase 4: Overall assessment of the relationship between drug product formulation, mucociliary clearance, interindividual variability, and regional drug absorption.Phase 5: Preparation of manuscripts, which is intended to be done in the third year of the grant, and is the reason for the reduced budget for that year. 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