Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties

Rygg, Alex D.; Hindle, Michael; Longest, P. Worth

doi:10.1007/s11095-015-1837-5

Cited by 30 publications

(27 citation statements)

References 61 publications

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“…Both ICS molecules are considered to be extremely lipophilic, with octanol/water partition coefficients on the order of 5000 or above (40). As a result, the epithelial surface was assumed to provide no resistance to absorption and the surface boundary condition was Y i,wall = 0.…”

Section: Methodsmentioning

confidence: 99%

“…Based on the need to better understand epithelial absorption of inhaled medications, Rygg, Hindle and Longest (40–42) recently developed a dissolution, absorption and clearance (DAC) computational fluid dynamics (CFD) model of deposited ICS particles in the nasal cavity that resolved 3D transport in the airway surface liquid (ASL) over time. Advantages of this CFD model were the inclusion of clearance together with spatially heterogeneous particle and dissolved drug concentration profiles.…”

Section: Introductionmentioning

confidence: 99%

“…The study of Rygg and Longest (42) developed the nasal DAC model and validated results with in vivo nasal clearance (43) and in vitro ICS dissolution(35) data. Rygg et al (40) evaluated the effect of ICS microparticle size in the range of 1–5 μm on nasal epithelial uptake. Surprisingly, very heterogeneous patterns of nasal epithelial uptake were identified that were influenced by the size of the ICS particles leading to the conclusion that ICS sprays treat the nasal surface in a very nonuniform manner.…”

Section: Introductionmentioning

confidence: 99%

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Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

Longest

Hindle

2017

Pharm Res

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Purpose To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms. Methods A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP). Within G13, total epithelial absorption efficiency (AE) and dose uniformity (microdosimetry) were evaluated. Results Conventional microparticles resulted in very poor AE of FP (0.37%) and highly nonuniform epithelial absorption, such that <5% of cells received drug. Nanoaggregates improved AE of FP by a factor of 57-fold and improved dose delivery to reach approximately 40% of epithelial cells. True nanoaerosol resulted in near 100% AE for both drugs and uniform drug delivery to all cells. Conclusions Current ICS therapies are absorbed by respiratory epithelial cells in a highly nonuniform manner that may partially explain poor clinical performance in the small airways. Both nanoaggregates and nanoaerosols can significantly improve ICS absorption efficiency and uniformity.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

Longest

Hindle

2017

Pharm Res

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“…Details related to this model can be found in the previous studies by Rygg and Longest 18 and Rygg et al 19 Briefly, an anatomically-accurate surface model of the nasal cavity was created by mapping nasal morphometric data from Xi et al 20,21 onto a flat surface. At a given distance from the nostril, the width of the surface model was set equal to the cross-sectional perimeter of the nasal airway; this provided a base for a computational mesh representative of the nasal mucus (or airway surface liquid, ASL) layer.…”

Section: Methodsmentioning

confidence: 99%

“…The effect of drug particle size was previously considered with the nasal-DAC model in terms of microdosimetry and total nasal uptake. 19 These results are now extended to explore the effect of drug particle size in the nasal suspension formulation on plasma concentration, which is a common endpoint with in vivo PK assessments. The results of this study are intended to help understand the relationship between the shape of a plasma concentration profile and the regional distribution of drug in the nose following administration of a suspension formulation with a nasal spray device.…”

Section: Introductionmentioning

confidence: 99%

Linking Suspension Nasal Spray Drug Deposition Patterns to Pharmacokinetic Profiles: A Proof-of-Concept Study Using Computational Fluid Dynamics

Rygg

Hindle

Longest

2016

Journal of Pharmaceutical Sciences

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The objective of this study is to link regional nasal spray deposition patterns of suspension formulations, predicted with computational fluid dynamics (CFD), to in vivo human pharmacokinetic (PK) plasma concentration profiles. This is accomplished through the use of CFD simulations coupled with compartmental PK modeling. Results showed a rapid initial rise in plasma concentration that is due to the absorption of drug particles deposited in the nasal middle passages, followed by a slower increase in plasma concentration that is governed by the transport of drug particles from the nasal vestibule to the middle passages. Although drug deposition locations in the nasal cavity had a significant effect on the shape of the concentration profile, the absolute bioavailability remained constant provided that all of the drug remained in the nose over the course of the simulation. Loss of drug through the nostrils even after long time periods resulted in a significant decrease in bioavailability and increased variability. The results of this study quantify how differences in nasal drug deposition affect transient plasma concentrations and overall bioavailability. These findings are potentially useful for establishing bioequivalence for nasal spray devices and reducing the burden of in vitro testing, pharmacodynamics and clinical studies.

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Generating Model Integrated Evidence for Generic Drug Development and Assessment

Zhao

Kim

Zhang

et al. 2019

Clin Pharma and Therapeutics

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Quantitative methods and modeling (QMM) covers a broad spectrum of tool sets, of which physiologically based models and quantitative clinical pharmacology are most critical for generic drugs. QMM has been increasingly applied by the US Food and Drug Administration (FDA) to facilitating generic drug development and review, and has played a critical role in the modernization of bioequivalence (BE) assessment, especially for locally acting drug products, complex products of other types, and modified-release solid oral dosage forms. QMM has aided the development of novel BE methods, in vitro-only BE approaches, and risk-based evaluations. The future of QMM is model integrated evidence or virtual BE studies that can potentially provide pivotal information for generic drug approval. In summary, QMM is indispensable in modernizing generic drug development, BE assessment, and regulatory decision makings. Regulatory examples demonstrate how QMM can be used in modernizing generic drug development, addressing challenges in BE assessment, and supporting regulatory decision making.New drug development and approval depends on sufficient in vitro and in vivo evidence to support the regulatory assessment of drug product efficacy and safety. A generic drug is approved on the basis of sufficient demonstration of sameness to the corresponding brand drug. For both new and generic drugs, quantitative methods and modeling (QMM) can accelerate product development and regulatory assessment.For both new and generic drug development and approval, a mathematical model can be thought of as a knowledge management system that integrates all scientific understanding and existing data about a drug product regarding its formulation, in vitro/in vivo release, pharmacokinetics (PK), pharmacodynamics (PD), and clinical responses. The discipline of QMM both builds these models and uses them to aid both regulatory and business decisions. QMM in new drug developmentFor new drug development, as shown in Figure 1, the data axis includes information and datasets collected through the full Research and Development course for the active pharmaceutical ingredient (API), formulation, in vitro release, the targeted in vivo release profile, animal and human drug PK, PD response(s), and clinical responses in terms of both efficacy and safety end points. Models describing the relationships between the datasets are captured in the model axis. The use of these models can accelerate decisions and optimize the collection of data.Model-informed drug development (MIDD) under the Prescription Drug User Fee Amendments of 2017 (PDUFA VI) is an initiative to use these models to decrease development uncertainty, cost, time, attritions, and failure rates. It aims to inform drug development and regulatory decision makings by using population PK, dose/exposure-response relationships, and biological and statistical models derived from preclinical and clinical data sources. An MIDD pilot program was launched with goals to provide an opportunity for drug developers and the FDA t...

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Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties

Cited by 30 publications

References 61 publications

Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

Linking Suspension Nasal Spray Drug Deposition Patterns to Pharmacokinetic Profiles: A Proof-of-Concept Study Using Computational Fluid Dynamics

Generating Model Integrated Evidence for Generic Drug Development and Assessment

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