Quantifying Agglomerate-to-Wall Impaction in Dry Powder Inhalers.

PURPOSE: The probability of agglomerate-to-wall collision was quantified using a unique image processing technique applied to high-speed microscopic images. The study aimed to investigate the effects of flow rate and particle size on the percentage of colliding agglomerates detected within an in-house powder dispersion device. METHOD: The device consists of a swirl chamber and two tangential inlets in various configurations, designed to emulate the geometric features of commercial devices such as the Aerolizer® and Osmohaler®. The test cases were conducted with constant flow rates of 30 SLPM and 60 SLPM. Four powder samples were tested, including carrier Respitose® SV010 (median volume diameter 104 µm, span 1.7) and mannitol of three constituent primary particle sizes (3 µm, 5 µm and 7 µm; span 1.6 - 1.9). RESULTS: At the lower flow rate of 30 SLPM, collision frequencies were significantly different between powders of different constituent particle sizes, but the effects of powder properties diminished on increasing the flow rate to 60 SLPM. At the higher flow rate, all powders experienced a significant increase in the proportion of colliding particles. CONCLUSION: Analysis of collision events showed that the probability of collision for each agglomerate increased with agglomerate diameter and velocity. Experimental data of agglomerate-to-wall collision were utilised to develop a logistic regression model that can accurately predict collisions with various powders and flow rates.

Application of a Thermosensitive In Situ Gel of Chitosan-Based Nasal Spray Loaded with Tranexamic Acid for Localised Treatment of Nasal Wounds.

The integrity of the nasal epithelium plays a crucial role in the airway defence mechanism. The nasal epithelium may be injured as a result of a large number of factors leading to nose bleeds, also known as epistaxis. However, local measures commonly used to treat epistaxis and improve wound healing present several side effects and patient discomfort. Hence, this study aims to address some of these drawbacks by developing a new formulation for nasal epithelial wound healing. Chitosan, a biodegradable and biocompatible polymer, was used to develop a thermosensitive nasal formulation for the delivery of tranexamic acid (TXA), one of the most effective pharmacological options to control bleeding with cost and tolerability advantages. The in situ gelation properties of the formulation upon administration in the nasal cavity were investigated in terms of gelation time and temperature. It was found that the developed formulation can undergo rapid liquid-to-gel phase change within approximately 5 min at 32°C, which is well within the human nasal cavity temperature range. The spray pattern, deposition and droplet size generated by the nasal spray was also characterised and were found to be suitable for nasal drug delivery. It was also observed that the in situ gelation of the formulation prevent nasal runoff, while the majority of drug deposited mainly in the anterior part of the nose with no lung deposition. The developed formulation was shown to be safe on human nasal epithelium and demonstrated six times faster wound closure compared to the control TXA solution.

Effects of the deformation and size of the upper airway on the deposition of aerosols.

Aerosol drug delivery in the human airway is significantly affected by the morphology and size of the airway. This work developed a CFD-DEM model to simulate and analyze air flow and powder dynamics in combined inhaler-airway systems with different degrees of airway deformation (non-deformed, 50%, and 75% deformed) and sizes (adult, 0.80, and 0.62 scaled). The airways were generated based on a regular airway constructed from the MRI images through finite element method (for deformed airways) or scaling-down (for smaller airways). The airways were connected to Turbuhaler® through a connector. The results showed that under the same flow rate, the variation in the airway geometry and size had a minimum impact on the flow field and powder deposition in the device and the connector. However, deformation caused more particle deposition in the deformed region. Notably, the airway with 50% deformation had the most particles passing through the airway with the largest particle sizes due to its lower air velocity in the deformed area. Reducing airway size resulted in more powder deposition on the airway, particularly at the pharynx and mouth regions. This was because, with the same flow rate, the flow velocity in the smaller airway was higher, causing more particle-wall collisions in the mouth and pharynx regions. More importantly, the deposition efficiency in the 0.62-scaled airway was significantly higher than the other two airways, highlighting the importance of the different administration of aerosol drugs for young children.

Effects of the mouthpiece and chamber of Turbuhaler® on the aerosolization of API-only powder formulations.

Powder dispersion in dry powder inhalers (DPIs) is affected by powder formulations as well as the design of a device. This paper conducted a numerical investigation based on the coupled computational fluid dynamics (CFD) and discrete element method (DEM) to evaluate the changes of the design of a commercial DPI device Turbuhaler® on the aerosolization of an API-only formulation. Six different designs were proposed by modifying the mouthpiece and chamber of the original geometry which was reconstructed from a CT-scan of the Turbuhaler, and their performances in terms of powder deposition in the device and fine powder fraction (FPF) were evaluated. The resistance of the device was observed to vary with different designs. For the change of the mouthpiece, the device with a cylindrical mouthpiece had the least resistance and the lowest FPF emitted among all the devices, confirming the important role of the spiral mouthpiece on powder dispersion. Reducing the mouthpiece size caused more powder deposition in the inhaler due to higher airflow velocity, but FPF emitted increased compared to the original design as more powder dispersion occurred inside the mouthpiece. The half-length mouthpiece design reduced device resistance to increase airflow velocity and average collision energy, resulting in an increase in FPF loaded but a decrease in the number of collisions. For the change of the chamber, the domed chamber design increased the powder dispersion time and thus enhanced the frequency and energy of particle collisions, which eventually led to an increase in FPF loaded. At fixed flow rates, the powder dispersion efficiency was a function of the device resistance with higher device resistance causing an increase in the FPF loaded. However, it is important for the patient's attainable pressure drop to be considered in this context. Correlations between the aerosolization efficiency and the ratio of the average collision energy and cohesion energy were established based on model-predicted quantities.

In vitro interactions of aerosol formulations with human nasal epithelium using real-time monitoring of drug transport in a nasal mucosa-on-a-chip.

The current organ-on-chip platforms used for studying respiratory drug delivery are limited to the administration of drug solutions and suspensions, lacking the in vivo aerosol drug administration and aerosol interaction with the respiratory tract barrier. Moreover, they mostly rely on conventional assays that require sample collection and 'off the chip' analyses, which can be labor-intensive and costly. In this study, a human nasal epithelial mucosa (NEM)-on-a-chip is developed that enables the deposition of aerosolized nasal formulations while emulating realistic shear stresses (0.23 and 0.78 Pa), exerted to the inferior and middle turbinate of the human nasal cavity. Under these different dynamic conditions in the donor channel of the NEM-on-a-chip, the deposited dose of aerosols and particle size distributions varied. In addition, the increase in the shear stress to 0.78 Pa adversely affected the cells' viability, reflected by a 36.9 ± 5.4% reduction in the transepithelial electrical resistance. The epithelial transport profiles of aerosolized ibuprofen formulations under 0.23 Pa shear stress were successfully monitored in real-time by an electrochemical sensor embedded in the acceptor channel, where the NEM-on-a-chip was able to monitor the effect of permeation enhancer in the test formulation on the rate of drug transport. The novel NEM-on-a-chip can potentially be a promising physiologically relevant tool for reliable nasal aerosol testing in vitro.

Challenges in the Development and Application of Organ-on-Chips for Intranasal Drug Delivery Studies.

With the growing demand for the development of intranasal (IN) products, such as nasal vaccines, which has been especially highlighted during the COVID-19 pandemic, the lack of novel technologies to accurately test the safety and effectiveness of IN products in vitro so that they can be delivered promptly to the market is critically acknowledged. There have been attempts to manufacture anatomically relevant 3D replicas of the human nasal cavity for in vitro IN drug tests, and a couple of organ-on-chip (OoC) models, which mimic some key features of the nasal mucosa, have been proposed. However, these models are still in their infancy, and have not completely recapitulated the critical characteristics of the human nasal mucosa, including its biological interactions with other organs, to provide a reliable platform for preclinical IN drug tests. While the promising potential of OoCs for drug testing and development is being extensively investigated in recent research, the applicability of this technology for IN drug tests has barely been explored. This review aims to highlight the importance of using OoC models for in vitro IN drug tests and their potential applications in IN drug development by covering the background information on the wide usage of IN drugs and their common side effects where some classical examples of each area are pointed out. Specifically, this review focuses on the major challenges of developing advanced OoC technology and discusses the need to mimic the physiological and anatomical features of the nasal cavity and nasal mucosa, the performance of relevant drug safety assays, as well as the fabrication and operational aspects, with the ultimate goal to highlight the much-needed consensus, to converge the effort of the research community in this area of work.

Numerical analysis of airflow and particle deposition in multi-fidelity designs of nasal replicas following nasal administration.

BACKGROUND AND OBJECTIVE: An improved understanding of flow behaviour and particle deposition in the human nasal airway is useful for optimising drug delivery and assessing the implications of pollutants and toxin inhalation. The geometry of the human nasal cavity is inherently complex and presents challenges and manufacturing constraints in creating a geometrically realistic replica. Understanding how anatomical structures of the nasal airway affect flow will shed light on the mechanics underpinning flow regulation in the nasal pharynx and provide a means to interpret flow and particle deposition data conducted in a nasal replica or model that has reduced complexity in terms of their geometries. This study aims to elucidate the effects of sinus and reduced turbinate length on nasal flow and particle deposition efficiencies. METHODS: A complete nasal airway with maxillary sinus was first reconstructed using magnetic resonance imaging (MRI) scans obtained from a healthy human volunteer. The basic model was then modified to produce a model without the sinus, and another with reduced turbinate length. Computational fluid dynamics (CFD) was used to simulate flow in the nasal cavity using transient flow profiles with peak flow rates of 15 L/min, 35 L/min and 55 L/min. Particle deposition was investigated using discrete phase modelling (DPM). RESULTS: Results from this study show that simplifying the nasal cavity by removing the maxillary sinus and curved sections of the meatus only has a minor effect on airflow. By mapping the spatial distribution of monodisperse particles (10 µm) in the three models using a grid map that consists of 30 grids, this work highlights the specific nasal airway locations where deposition efficiencies are highest, as observed within a single grid. It also shows that lower peak flow rates result in higher deposition differences in terms of location and deposition quantity, among the models. The highest difference in particle deposition among the three nasal models is ∼10%, and this is observed at the beginning of the middle meatus and the end of the pharynx, but is only limited to the 15 L/min peak flow rate case. Further work demonstrating how the outcome may be affected by a wider range of particle sizes, less specific to the pharmaceutical industries, is warranted. CONCLUSION: A physical replica manufactured without sections of the middle meatus could still be adequate in producing useful data on the deposition efficiencies associated with an intranasal drug formulation and its delivery device.

Understanding the effects of inhaler resistance on particle deposition behaviour - A computational modelling study.

BACKGROUND AND OBJECTIVE: Understanding the impact of inhaler resistance on particle transport and deposition in the human upper airway is essential for optimizing inhaler designs, thereby contributing to the enhancement of the therapeutic efficacy of inhaled drug delivery. This study demonstrates the potential effects of inhaler resistance on particle deposition characteristics in an anatomically realistic human oropharynx and the United States Pharmacopeia (USP) throat using computational fluid dynamics (CFD). METHOD: Magnetic resonance (MR) imaging was performed on a healthy volunteer biting on a small mockup inhaler mouthpiece. Three-dimensional geometry of the oropharynx and mouthpiece were reconstructed from the MR images. CFD simulations coupled with discrete phase modelling were conducted. Inhaled polydisperse particles under two different transient flow profiles with peak inspiratory flow rates (PIFR) of 30 L/min and 60 L/min were investigated. The effect of inhaler mouthpiece resistance was modelled as a porous medium by varying the initial resistance (Ri) and viscous resistance (Rv). Three resistance values, 0.02 kPa0.5minL-1, 0.035 kPa0.5minL-1 and 0.05 kPa0.5 minL-1, were simulated. The inhaler outlet velocity was set to be consistent across all models for both flow rate conditions to enable a meaningful comparison of models with different inhaler resistances. RESULT: The results from this study demonstrate that investigating the effect of inhaler resistance by solely relying on the USP throat model may yield misleading results. For the geometrically realistic oropharyngeal model, both the pressure and kinetic energy profiles at the mid-sagittal plane of the airway change dramatically when connected to a higher-resistance inhaler. In addition, the geometrically realistic oropharyngeal model appears to have a resistance threshold. When this threshold is surpassed, significant changes in flow dynamics become evident, which is not observed in the USP throat model. Furthermore, this study also reveals that the impact of inhaler resistance in a geometrically realistic throat model extends beyond the oral cavity and affects particle deposition downstream of the oral cavity, including the oropharynx region. CONCLUSION: Results from this study suggest that key mechanisms underpinning the working principles of inhaler resistance are intricately connected to their complex interaction with the pharynx geometry, which affects the local pressure, local variation in velocity and kinetic energy profile in the airway.

From laminar to turbulent flow in a dry powder inhaler: The effect of simple design modifications.

In order to better understand powder dispersion in dry powder inhaler (DPI) devices, a new powder disperser was designed, which uses flow modifiers to alter powder fluidization behavior so as to physically replicate various flow conditions observed in a range of commercial DPIs. The influence of these modifiers on the performance of the DPI was analyzed for flowrates progressing from laminar (15 L/min) to transitional (30 L/min), and finally turbulent flow regimes (60 L/min) in the device. The aerosol performance of the disperser was measured using a Next Generation Impactor. For flowrate in the laminar regime, powder evacuation from the disperser was generally insufficient (<30%), which was increased to >85% when the device was operated in the turbulent flow regime. In contrast, the highest fine particle fraction (FPF) and lowest throat deposition were achieved when operating in the transitional flow regime. The FPF could be increased further by applying flow modifications such as narrowing the air passage before the powder pocket, inducing localized turbulence (by a grid) near the powder pocket, and by changing the loading position of the powder. Flow modifiers had the most noticeable effect under a laminar flow regime, however, the device operated most efficiently under a transitional flow regime.

Application of Micro-Engineered Kidney, Liver, and Respiratory System Models to Accelerate Preclinical Drug Testing and Development.

Developing novel drug formulations and progressing them to the clinical environment relies on preclinical in vitro studies and animal tests to evaluate efficacy and toxicity. However, these current techniques have failed to accurately predict the clinical success of new therapies with a high degree of certainty. The main reason for this failure is that conventional in vitro tissue models lack numerous physiological characteristics of human organs, such as biomechanical forces and biofluid flow. Moreover, animal models often fail to recapitulate the physiology, anatomy, and mechanisms of disease development in human. These shortfalls often lead to failure in drug development, with substantial time and money spent. To tackle this issue, organ-on-chip technology offers realistic in vitro human organ models that mimic the physiology of tissues, including biomechanical forces, stress, strain, cellular heterogeneity, and the interaction between multiple tissues and their simultaneous responses to a therapy. For the latter, complex networks of multiple-organ models are constructed together, known as multiple-organs-on-chip. Numerous studies have demonstrated successful application of organ-on-chips for drug testing, with results comparable to clinical outcomes. This review will summarize and critically evaluate these studies, with a focus on kidney, liver, and respiratory system-on-chip models, and will discuss their progress in their application as a preclinical drug-testing platform to determine in vitro drug toxicology, metabolism, and transport. Further, the advances in the design of these models for improving preclinical drug testing as well as the opportunities for future work will be discussed.

Simulating the effect of individual upper airway anatomical features on drug deposition.

This study aims to systematically isolate different anatomical features of the human pharynx with the goal to investigate their independent influence on airflow dynamics and particle deposition characteristics in a geometrically realistic human airway. Specifically, the effects of the uvula, epiglottis and soft palate on drug particle deposition are studied systematically, by carefully removing each of these anatomical features from reconstructed models based on MRI data and comparing them to a benchmark realistic airway model. Computational Fluid Dynamics using established turbulence models is employed to simulate the transport of mono-dispersed particles (3 µm) in the airway at two flow-rates. The simulations suggest three findings: 1) widening the space between the oral cavity and oropharynx and where the soft palate is situated leads to the most dramatic reduction in drug deposition in the upper airway; 2) exclusion of the uvula and epiglottis: a) affects flow dynamics in the airway; b) alters regional deposition behaviour; c) does not significantly affect the total number of particles deposited in the pharynx; and 3) the space adjacent to the soft palate is a key determinant for aerosol deposition in the extrathoracic region and is related to mechanisms of flow acceleration, diversion and recirculation.

Effects of respiratory rate on the fluid mechanics of a reconstructed upper airway.

This study aims to utilise particle image velocimetry (PIV) techniques to investigate the time-dependant effects of respiratory rate in the extrathoracic airway, to show how they affect the flow field developed. There has been limited validation of computational fluid dynamics (CFD) models using experimental setups. Furthermore, the large majority of existing CFD models focus on rigid airways, not accounting for active deformation through the breathing cycle. Experiments were carried out to expand upon Zhao et al.'s previous study, in which a single respiratory rate was investigated. This studied utilised a transient, sinusoidal flow profile with two respiratory rates of 10 breaths per minute (BPM) and 25 BPM, both achieving a maximum flow rate correlating to 5 L/min in air to simulate tidal breathing. Results from this study showed that respiratory rate had the greatest influence near the onset of the inspiratory and expiratory manoeuvres, with the higher respiratory rate homogenising later in the cycle. It was shown that airway deformation at the level of the soft palate homogenised flow downstream of the deformation which resulted in a lower peak magnitude velocity for approximately 40% of the cycle at the level of the epiglottis, when compared to the rigid airway model.

Effect of inflow conditioning for dry powder inhalers.

The transport of pharmaceutical dry powder inside an optically accessible inhaler-like device is studied using both macro- and microscopic high-speed imaging. The investigation aims to systematically study the effect of inflow modifications on the dispersion characteristics of agglomerates inside a dry powder inhaler (DPI) geometry. An inhaler device was designed with geometrical features akin to commercial inhalers used in the current market and research oriented inhalers such as the Twincer®: two offset inlet channels (one with a powder pocket), a clockwise swirling chamber and a single outlet channel. At the device outlet, a vacuum pump was fitted with an actuator and calibrated to achieve a steady state inhalation with a peak flowrate of 85 and 125 L/min. Airflow conditions at the intake of the device were strategically perturbed in order to induce powder fluidisation and dispersion using turbulence grids and through physically obstructing channel streams in order to achieve changes in flow behaviour (e.g., flow separation). Complete fluidisation of the powder bed was observed with image processing enabling statistics on de-agglomerated fragment size and velocity. A range of behaviour was noted including local turbulence through introduction of a grid, bimodal fragment size behaviour for cohesive mannitol powder, as well as introduction of low velocity zones in the device through flow splitting. The geometry enables simple systematic study of inflow conditions into a DPI-like device with the data being useful for study of a given powder formulation (mannitol) and validation of computational models.

Real-time quantitative monitoring of in vitro nasal drug delivery by a nasal epithelial mucosa-on-a-chip model.

OBJECTIVES: A human nasal epithelial mucosa (NEM) on-a-chip is developed integrated with a novel carbon nanofibers-modified carbon electrode for real-time quantitative monitoring of in vitro nasal drug delivery. The integration of platinum electrodes in the chip also enables real-time measurement of transepithelial electrical resistance (TEER). METHODS: The air-liquid interface culture of nasal epithelial RPMI 2650 cells in the NEM-on-a-chip was optimized to mimic the key functional characteristics of the human nasal mucosa. The epithelial transport of ibuprofen in the NEM-on-a-chip was electrochemically monitored in real-time under static and physiologically realistic dynamic flow conditions. RESULTS: The NEM-on-a-chip mimics the mucus production and nasal epithelial barrier function of the human nasal mucosa. The real-time drug quantification by the NEM-on-a-chip was validated versus the high-performance liquid chromatography method. The drug transport rate monitored in the NEM-on-a-chip was influenced by the flow in the bottom compartment of the chip, highlighting the importance of emulating the dynamic in vivo condition for nasal drug transport studies. CONCLUSION: This novel NEM-on-a-chip can be a low-cost and time-efficient alternative to the costly laborious conventional techniques for in vitro nasal drug transport assays. Importantly, its dynamic microenvironment enables conducting nasal drug transport tests under physiologically relevant dynamic conditions.

Non-intrusive high resolution in-vitro measurement of regional drug powder deposition.

Optical Coherence Tomography (OCT) is a high-resolution and non-invasive cross-sectional imaging technique mainly used for medical imaging and industrial non-destructive testing. However, its feasibility in the quantification of pulmonary drug deposition has not been investigated. In this study, an optically accessible airway model of the upper airway and the tracheobronchial tree was used, and experiments were performed at flow rates of 40 L/min, 60 L/min and 80 L/min. Drug deposition in different regions of the airway cast has been determined and quantified from OCT images of the deposition layer. Regionally resolved measurement of deposition shows that flow rate has a significant effect (p = 0.04) on the average thickness of the deposition layer in the upper airway but not in the tracheobronchial tree under these test conditions. These localized and high-resolution measurements of deposition also demonstrate that the flow rate can influence the spatial uniformity of the deposition layer. The technique is able to provide significant regional drug deposition details, including the thickness, spatial deposition pattern and micro-cavities in the deposition layer, that would potentially serve to assess the efficacy of inhalation drug delivery systems.

The effects of upper airway tissue motion on airflow dynamics.

The human upper airway is not only geometrically complex, but it can also deform dynamically as a result of active muscle contraction and motility during respiration. How the active transformation of the airway geometry affects airflow dynamics during respiration is not well understood despite the importance of this knowledge towards improving current understanding of particle transport and deposition. In this study, particle imaging velocimetry (PIV) measurements of the fluid dynamics are presented in a physiologically realistic human upper airway replica for (i) the undeformed case and (ii) the case where realistic soft tissue motion during breathing is emulated. Results from this study show that extrathoracic wall motion alters the flow field significantly such that the fluid dynamics is distinctly different from the undeformed airway. Distinctive flow field patterns in the physiologically realistic airway include (i) fluid recirculation at the back of the tongue and cranial to the tip of the epiglottis during mid-inspiration, (ii) horizontal and posteriorly directed flow at the back of tongue at the peak of inspiration and (iii) a more homogeneous flow across the airway downstream from the epiglottis. These findings suggest that the active deformation of the human upper airway may potentially influence particle transport and deposition at the back of the tongue and therefore, highlights the importance of considering extrathoracic wall motion in future airway flow studies. D.

Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders.

BACKGROUND: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated. METHODS: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics. RESULTS: The formulations showed rapid gelation (4-7 min) at 30-35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110-150 kDa led to generation of optimum spray with lower Dv50, wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions. CONCLUSIONS: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.

Does upper airway deformation affect drug deposition?

Knowledge that enables the accurate simulation of drug deposition in the human upper airway is necessary to develop robust platforms for efficient drug delivery by inhalation devices. The human upper airway is deformable during inhalation but how it could affect the deposition of inhaled drugs is unknown. We aimed to determine whether pharyngeal deformation at the soft palate level would have any significant effects on throat deposition, in vitro lung dose and fine particle fraction. In this study, dry mannitol powders were delivered to the next-generation cascade impactor (NGI) through the United States Pharmacopeia (USP) throat, and a realistic upper airway cast (RUPAC) at flow rates of 40, 60 and 80 L min-1. Deformation of the upper airway at 25%, 50%, and 75% in the lateral and antero-posterior directions were experimentally simulated in the RUPAC. Throat deposition (p = 0.04) is significantly affected when the upper airway deforms laterally but not antero-posteriorly.