Combined in Vitro-in Silico Approach to Predict Deposition and Pharmacokinetics of Budesonide Dry Powder Inhalers.

PURPOSE: A combined in vitro - in silico methodology was designed to estimate pharmacokinetics of budesonide delivered via dry powder inhaler. METHODS: Particle size distributions from three budesonide DPIs, measured with a Next Generation Impactor and Alberta Idealized Throat, were input into a lung deposition model to predict regional deposition. Subsequent systemic exposure was estimated using a pharmacokinetic model that incorporated Nernst-Brunner dissolution in the conducting airways to predict the net influence of dissolution, mucociliary clearance, and absorption. RESULTS: DPIs demonstrated significant in vitro differences in deposition, resulting in large differences in simulated regional deposition in the central conducting airways and the alveolar region. Similar but low deposition in the small conducting airways was observed with each DPI. Pharmacokinetic predictions showed good agreement with in vivo data from the literature. Peak systemic concentration was tied primarily to the alveolar dose, while the area under the curve was more dependent on the total lung dose. Tracheobronchial deposition was poorly correlated with pharmacokinetic data. CONCLUSIONS: Combination of realistic in vitro experiments, lung deposition modeling, and pharmacokinetic modeling was shown to provide reasonable estimation of in vivo systemic exposure from DPIs. Such combined approaches are useful in the development of orally inhaled drug products.

Comparison of in vitro deposition of pharmaceutical aerosols in an idealized child throat with in vivo deposition in the upper respiratory tract of children.

PURPOSE: Deposition of drug emitted from two commercially available inhalers was measured in an in vitro child oral airway model and compared to existing in vivo data to examine the ability of the child model to replicate in vivo deposition. METHODS: In vitro deposition of drug from a QVAR® pressurized metered dose inhaler (pMDI) and Pulmicort® Turbuhaler® dry powder inhaler (DPI) in an Idealized Child Throat (1) and downstream filter was measured using UV spectroscopy and simulated realistic breathing profiles. Potential effects of ambient relative humidity ranging from 10% to 90% on deposition were also considered. RESULTS: In vitro QVAR pMDI deposition in the idealized mouth-throat at 50% RH (39.2 ± 2.3% of delivered dose) compared well (p>0.05) with in vivo extrathoracic deposition in asthmatic children age 8 to 14 (45.8 ± 12.3%). In vitro Turbuhaler DPI deposition in the idealized mouth-throat at 50% RH (69.0 ± 1.5%) matched in vivo extrathoracic deposition (p>0.05) in 6 to 16 year old children with cystic fibrosis (70.4 ± 21.2%). The effects of ambient humidity were found to be insignificant for Turbuhaler and minor for QVAR. CONCLUSIONS: The Idealized Child Throat successfully mimics in vivo deposition data in school age children for the inhalers tested, and may provide a standard platform for optimizing pediatric treatment with inhaled pharmaceutical aerosols.

Size-specific filtration efficiency and pressure drop of school-aged children's woven and nonwoven masks at varying face velocities.

BACKGROUND: Differences in physiology and breathing patterns between children and adults lead to disparate responses to aerosols of varying sizes. No standardized method exists for measuring the filtration efficiency (FE) of children's masks to reflect such differences. METHODS: Using an adult N95 mask as a control and two different face velocities (vf) (9.3 cm/s representing adults and 4.0 cm/s representing school-aged children), we tested the pressure drop (ΔP) through children's nonwoven masks (surgical and KN95) and children's woven masks (100% cotton and partially-cotton-based masks), as well as their size-specific FE between aerodynamic particle diameters of 0.02 and 2.01 µm. RESULTS: All three types of mask showed a 1 to 9% absolute increase in minimum FE at the lower vf and a significant decrease in ΔP. For children's surgical masks the increase in FE was significant for most of the examined particle sizes, but for children's woven masks the increase was limited to particles smaller than 0.04 µm. CONCLUSIONS: Lower vf for children is likely to lead to a higher FE, lower ΔP, and consequently higher filter qualities in children's masks. For woven masks, the FE for particles larger than 0.04 µm was low (typically <50%) for both vf's studied.

Inhalation delivery of nucleic acid gene therapies in preclinical drug development.

INTRODUCTION: Inhaled gene therapy programs targeting diseases of the lung have seen increasing interest in recent years, though as of yet no product has successfully entered the market. Preclinical research to support such programs is critically important in maximizing the chances of developing successful candidates. AREAS COVERED: Aspects of inhalation delivery of gene therapies are reviewed, with a focus on preclinical research in animal models. Various barriers to inhalation delivery of gene therapies are discussed, including aerosolization stresses, aerosol behavior in the respiratory tract, and disposition processes post-deposition. Important aspects of animal models are considered, including determinations of biologically relevant determinations of dose and issues related to translatability. EXPERT OPINION: Development of clinically-efficacious inhaled gene therapies has proven difficult owing to numerous challenges. Fit-for-purpose experimental and analytical methods are necessary for determinations of biologically relevant doses in preclinical animal models. Further developments in disease-specific animal models may aid in improving the translatability of results in future work, and we expect to see accelerated interests in inhalation gene therapies for various diseases. Sponsors, researchers, and regulators are encouraged to engage in early and frequent discussion regarding candidate therapies, and additional dissemination of preclinical methodologies would be of immense value in avoiding common pitfalls.

Characterization of dry powder inhaler performance through experimental methods.

Experimental methods provide means for the quality control of existing DPIs and for exploring the influence of formulation and device parameters well in advance of clinical trials for novel devices and formulations. In this review, we examine the state of the art of in vitro testing of DPIs, with a focus primarily on the development of accurate in vitro-in vivo correlations. Aspects of compendial testing are discussed, followed by the influence of flow profiles on DPI performance, the characterization of extrathoracic deposition using mouth-throat geometries, and the characterization of regional thoracic deposition. Additional experimental methods that can inform the timing of bolus delivery, the influence of environmental conditions, and the development of electrostatic charge on aerosolized DPI powders are reviewed. We conclude with perspectives on current in vitro methods and identify potential areas for future investigation, including the estimation of variability in deposition, better characterization of existing compendial methods, optimization of formulation and device design to bypass extrathoracic deposition, and the use of novel tracheobronchial filters that aim to provide more clinically relevant measures of performance directly from in vitro testing.

Size-Specific Filtration Performance of N95 Respirators After Decontamination by Moist Heat Incubation.

Background: Decontamination and reuse of respirators have been proposed to mitigate the shortage of respirators during pandemics. The U.S. National Institute for Occupational Safety and Health (NIOSH)'s respirator filtration efficiency (FE) test has been used to confirm that decontamination procedures maintain minimum FE above 95% for N95s and similar respirators. However, it was hypothesized that the limited range of test particle sizes may not include the most penetrating particle size (MPPS) for all respirators, especially after decontamination by moist heat incubation (MHI). Materials and Methods: A custom-designed apparatus was used to measure size-specific FE for respirators across particle size bins between aerodynamic diameter of 0.07 and 1.97 µm using an electrical low-pressure impactor. FEs were measured for two N95 respirator models before and after 10 cycles of MHI. In addition, pressure drop through the respirator materials and scanning electron microscope (SEM) images of respirator layers were obtained before and after MHI. Results: For Kimtech™ brand N95 respirators, FE was not reduced at any size after MHI. For Safe Life brand N95s, FE was below 95% before MHI and decreased significantly after MHI. The MPPS for this respirator was outside the range defined in NIOSH test protocol, and increased after MHI. There was no appreciable change to the pressure drop through the two respirator models after MHI, nor was any deterioration in fiber integrity visible in SEM images. Conclusions: Based on the results of the present study and other studies in the literature, MHI can be used to decontaminate respirators without significant decrease in FE. However, potential effects of MHI on FE need to be assessed for each respirator model. The ability to evaluate size-specific FE across a wide range of particle sizes is important in identifying the MPPS and associated FE of respirators before and after MHI.

A simple HEPA filtering facepiece.

Shortages of efficient filtering facepiece respirators leave the public vulnerable to transmission of infectious diseases in small particle aerosols. This study demonstrates that a high-filtration-efficiency facepiece capable of filtering out >95% of 0.05µm particles while being worn can be simply produced with available materials.

An Exploration of Factors Affecting In Vitro Deposition of Pharmaceutical Aerosols in the Alberta Idealized Throat.

Background: The development of accurate in vitro-in vivo correlations requires the consideration of a number of factors in vitro, including the emulation of upper airway geometry, inhalation maneuver, inhaler orientation, and environmental conditions. In this study, we examine the effects of inhaler insertion angle and humidity on deposition from a number of marketed inhalers. Methods: Three dry-powder inhalers (DPIs; Pulmicort® Turbuhaler®, Budelin® Novolizer®, and Easyhaler® Budesonide) were examined at two insertion angles, one with the inhaler directed toward the back of the oral cavity, the other with the inhaler directed toward the tongue. Three pressurized metered-dose inhalers (pMDIs; QVAR®, Ventolin® Evohaler®, and Flovent® HFA) were examined considering the joint effects of insertion angle (as above) and relative humidity at low (15%-25%) and high (>95%) conditions. Deposited drug masses in an Alberta Idealized Throat and downstream filter were quantified through ultraviolet spectroscopy. Results and Conclusions: Three of six inhalers showed sensitivity to insertion angle. When directed toward the tongue versus the back of the mouth, the filter dose decreased from 21.9% to 15.6% (percent delivered dose) for Easyhaler Budesonide (p < 0.001), from 46.5% to 26.0% for Ventolin Evohaler (p < 0.001), and from 56.7% to 35.7% for Flovent HFA (p < 0.001) for tests at ambient laboratory humidity. Sensitivity to insertion angle and increases in total lung dose variability may be reduced in future products using larger diameter mouthpieces and smaller particles for DPIs and lower-momentum sprays for pMDIs. Humidity influenced deposition from Ventolin Evohaler and Flovent HFA. When oriented toward the back of the oral cavity, the filter dose decreased from 46.5% to 36.9% for Ventolin Evohaler (p = 0.005) and from 56.7% to 44.2% for Flovent HFA (p < 0.001) at high humidity relative to low. High humidity may cause a reduction in total in vitro lung doses for some pMDI aerosols.

Amorphous pullulan trehalose microparticle platform for respiratory delivery.

Spray drying biologics and small-molecule drugs can increase their thermal stability relative to liquid dosage forms and allow for widespread distribution to developing countries without cold chain infrastructure. In this study, pullulan trehalose powder is spray dried for inhalation. The powder is characterized in terms of manufacturability, physical stability, device compatibility, and aerosol performance. The manufacturability is demonstrated by reasonable spray drying yield and powder flowability. The powder has relatively low cohesiveness and high compressibility without semi-elastic deformation. Short-term physical stability for ambient temperature dry storage and 40 °C storage in commercial pressurized metered-dose inhaler propellants HFA 134a and HFA 227 is shown. A theoretical model predicts a high glass transition temperature near the surface of the microparticles where biologics are expected to reside. Emission from a commercial dry powder inhaler demonstrates high dispersibility, optimal size for inhalation, and adequate total lung dose, exceeding many commercial inhalation devices. The powder can be filled, stored, and actuated from a pressurized metered-dose inhaler without changes in particle morphology or solid phase. The pullulan trehalose platform thus appears promising for respiratory delivery.

An In Vitro Examination of the Effects of Altitude on Dry Powder Inhaler Performance.

BACKGROUND: The effects of altitude on dry powder inhaler (DPI) performance remain understudied. As existing standardized testing methodologies do not consider altitude, inhalation devices may be used in environments in which their performance has not been sufficiently characterized. METHODS: Six DPIs spanning a range of device resistances were examined in vitro in an environmental chamber mimicking a high-altitude environment equivalent to an altitude of 4200 m, with controls established at an altitude of 700 m. Deposition and size distribution data were quantified by using an Alberta Idealized Throat coupled to a Next-Generation Impactor, operated by using a square inhalation profile. Controls were established for two cases, one with a standard pressure drop and the other with a minimal efficacious flowrate. Experiments at simulated altitude were performed first by using a matched volumetric flowrate and second with a matched pressure drop, corresponding to values obtained in the controls. In vitro results were input into a lung deposition model to examine the relationship between particle-size distributions, inhalation flowrates, and regional deposition in the respiratory tract. RESULTS AND CONCLUSIONS: Simulated altitude caused statistically significant effects in some DPIs, but effects were variable, device dependent, and relatively minor. Medium-high resistance devices were more affected by the flowrate used to establish the control than by any effects of altitude. Patients able to generate sufficient inspiratory efforts can expect relatively consistent device performance at altitudes up to 4200 m for the devices examined here.

An Apparatus to Deliver Mannitol Powder for Bronchial Provocation in Children Under Six Years Old.

BACKGROUND: Currently bronchial provocation testing (BPT) using mannitol powder cannot be performed in children under 6 years. A primary reason is it is challenging for children at this age to generate a consistent inspiratory effort to inhale mannitol efficiently from a dry powder inhaler. A prototype system, which does not require any inhalation training from the pediatric subject, is reported here. It uses an external source of compressed air to disperse mannitol powder into a commercial holding chamber. Then the subject uses tidal breathing to inhale the aerosol. METHOD: The setup consists of a commercially available powder disperser and Volumatic™ holding chamber. Taguchi experimental design was used to identify the effect of dispersion parameters (flow rate of compressed air, time compressed air is applied, mass of powder, and the time between dispersion and inhalation) on the fine particle dose (FPD). The prototype was tested in vitro using a USP throat connected to a next generation impactor. The aerosols from the holding chamber were drawn at 10 L/min. A scaling factor for estimating the provoking dose to induce a 15% reduction in forced expiratory volume in 1 second (FEV1) (PD15) was calculated using anatomical dimensions of the human respiratory tract at various ages combined with known dosing values from the adult BPT. RESULTS: Consistent and doubling FPDs were successfully generated based on the Taguchi experimental design. The FPD was reliable over a range of 0.8 (±0.09) mg to 14 (±0.94) mg. The calculated PD15 for children aged 1-6 years ranged from 7.1-30 mg. The FPDs generated from the proposed set up are lower than the calculated PD15 and therefore are not expected to cause sudden bronchoconstriction. CONCLUSION: A prototype aerosol delivery system has been developed that is consistently able to deliver doubling doses suitable for bronchial provocation testing in young children.

Pediatric in vitro and in silico models of deposition via oral and nasal inhalation.

Respiratory tract deposition models provide a useful method for optimizing the design and administration of inhaled pharmaceutical aerosols, and can be useful for estimating exposure risks to inhaled particulate matter. As aerosol must first pass through the extrathoracic region prior to reaching the lungs, deposition in this region plays an important role in both cases. Compared to adults, much less extrathoracic deposition data are available with pediatric subjects. Recently, progress in magnetic resonance imaging and computed tomography scans to develop pediatric extrathoracic airway replicas has facilitated addressing this issue. Indeed, the use of realistic replicas for benchtop inhaler testing is now relatively common during the development and in vitro evaluation of pediatric respiratory drug delivery devices. Recently, in vitro empirical modeling studies using a moderate number of these realistic replicas have related airway geometry, particle size, fluid properties, and flow rate to extrathoracic deposition. Idealized geometries provide a standardized platform for inhaler testing and exposure risk assessment and have been designed to mimic average in vitro deposition in infants and children by replicating representative average geometrical dimensions. In silico mathematical models have used morphometric data and aerosol physics to illustrate the relative importance of different deposition mechanisms on respiratory tract deposition. Computational fluid dynamics simulations allow for the quantification of local deposition patterns and an in-depth examination of aerosol behavior in the respiratory tract. Recent studies have used both in vitro and in silico deposition measurements in realistic pediatric airway geometries to some success. This article reviews the current understanding of pediatric in vitro and in silico deposition modeling via oral and nasal inhalation.

The use of computational fluid dynamics in inhaler design.

INTRODUCTION: Computational fluid dynamics (CFD) has recently seen increased use in the design of pharmaceutical inhalers. The use of CFD in the design of inhalers is made difficult by the complex nature of aerosol generation. At present, CFD has provided valuable insight into certain aspects of inhaler performance, though limitations in computational power have prevented the full implementation of numerical methods in the design of inhalers. AREAS COVERED: This review examines the application of CFD in the design of aerosol drug delivery technologies with a focus on pressurized metered-dose inhalers (pMDI), nebulizers and dry powder inhalers (DPIs). Challenges associated with the application of CFD in inhaler design are discussed along with relevant investigations in the literature. Discussions of discrete element modeling (DEM) and the simulation of pharmaceutical aerosol dispersion are included. EXPERT OPINION: The extreme complexity of coupled fluid and aerosol dynamics associated with aerosol generation has somewhat limited the use of CFD in inhaler design. Combined CFD--DEM simulations provide a useful tool in the design of DPIs, though aerosol generation in pMDIs and nebulizers has eluded CFD modeling. The most beneficial use of CFD typically occurs when concurrent CFD and experimental analyses are performed, significantly enhancing the knowledge provided by experiment alone.