Effects of freebase/protonated nicotine concentration, liquid composition and electrical power on throat hit in direct-to-lung vaping: theory and clinical measurements.

BACKGROUND: For decades, the tobacco industry has engineered the sensory characteristics of combustible tobacco products including the degree of harshness experienced at the back of the throat. Commonly referred to as 'throat hit', this harshness derives from absorption of gas phase nicotine and other constituents by the sensory nerves. People who use tobacco products associate throat hit with the positive psychological effects of nicotine, making it a secondary reinforcer for smoking. On the other hand, high throat hit can make products aversive to naïve nicotine users and serves as a barrier to consumption of tobacco products. METHODS: We developed a first-principles theoretical model to predict nicotine absorption in the throat as a function of electronic nicotine delivery systems (ENDS) device power, liquid composition and puffing topography. The predicted nicotine absorption was compared with subjective throat harshness reported by human participants. We also simulated several ENDS use scenarios to identify the most important processes and factors that govern nicotine absorption in the throat. RESULTS: Across various ENDS configurations, we found that computed nicotine gas absorption in the throat was associated with subjective harshness scores (r=0.62; p<0.00001). We also found that liquid nicotine concentration, nicotine form, aerosol temperature and inhalation rate strongly influence nicotine absorption in the throat per unit of nicotine emitted by an ENDS. CONCLUSIONS: Nicotine throat hit can be predicted and manipulated through ENDS device and liquid design variables. Regulating ENDS throat hit is feasible and may help reduce product appeal to nicotine-naïve individuals while maintaining acceptability for smokers.

Anatomically-detailed segmented representative adult and pediatric nasal models for assessing regional drug delivery and bioequivalence with suspension nasal sprays.

In vitro nasal models can potentially facilitate development and approval of nasal drug products. This study aims to evaluate the potential for using regional deposition measurements from in vitro nasal models to evaluate nasal spray performance across several products. To accomplish this, the posterior regions of six anatomically realistic nasal airway models of adult and pediatric subjects, representing Low (L), Mean (M) and High (H) posterior drug deposition (PD) for each of the two age groups, were segmented with high anatomical precision into five regions of interest. These models were previously developed with the goal of quantifying the range of intersubject variability of PD following administration of inhaled corticosteroids. The in vitro regional drug deposition values were measured for the reference listed drug (RLD) product for triamcinolone acetonide and two corresponding generic (test) nasal spray products, as well as an RLD product for fluticasone furoate nasal spray. In general, the pediatric models mostly demonstrated higher PD compared to the adult models. The majority (>85 %) of PD was confined to the front and the inferior meatus regions. Subsequent population bioequivalence (PBE) analyses of the regional nasal deposition suggested that the anatomical differences among subjects may impact the nasal spray performance across different nasal products.

CFD-PK model for nasal suspension sprays: Validation with human adult in vivo data for triamcinolone acetonide.

The objectives of this study were to expand and implement a Computational Fluid Dynamics (CFD)-Dissolution, Absorption and Clearance (DAC)-Pharmacokinetics (PK) multi-physics modeling framework for simulating the transport of suspension-based nasal corticosteroid sprays. The mean CFD-predicted peak plasma concentration (Cmax) and area under the curve (AUC) of the plasma concentration-time profile, based on three representative nasal airway models (capturing low, medium and high posterior spray deposition), were within one standard deviation of available in vivo PK data for a representative corticosteroid drug (triamcinolone acetonide). The relative differences in mean Cmax between predictions and in vivo data for low dose (110 µg) and high dose (220 µg) cases were 27.8% and 10.1%, respectively. The models confirmed the dose-dependent dissolution-limited behavior of nasally delivered triamcinolone acetonide observed in available in vivo data. The total uptake from the nasal cavity decreased from 68.3% to 51.3% for the medium deposition model as dose was increased from 110 to 220 µg due to concentration-limited dissolution. The modeling framework is envisioned to facilitate faster development and testing of generic locally acting suspension nasal spray products due to its ability to predict the impact of differences in spray characteristics and patient use parameters on systemic PK.

Effects of Device Settings and E-Liquid Characteristics on Mouth-Throat Losses of Nicotine Delivered with Electronic Nicotine Delivery Systems (ENDS).

Currently it is not fully understood how the device settings and electronic liquid (e-liquid) composition, including their form of nicotine content, impact mouth and throat losses, and potentially lead to the variations in total nicotine delivery to the human lungs. An in situ size assessment method was developed for real-time measurements at the mouthpiece and outlet of a biorelevant mouth-throat to account for the dynamic nature of the aerosol. The aerosol size, temperature, and delivery through the mouth-throat replica and the exhaled aerosol between the puff intervals were measured at different wattages using various e-liquid compositions. The effects of body temperature and humidity on aerosol size and nicotine delivery were also explored to evaluate the importance of considering realistic in vivo conditions in in vitro measurements. Notably, in vitro tests with body temperature and humidity in mouth-throat model vs room conditions, resulted in larger aerosol size at the end of the throat (Dv50=5.83±0.33 µm vs 3.05±0.15 µm), significantly higher thoracic nicotine delivery (>90% vs 50-85%) potentially due to the lower exhaled amount (<10% vs 15-50%). Besides, higher VG/PG ratios resulted in significantly lower exhaled amount and higher mouth-throat nicotine deposition. One of the main outcomes of the study was finding significantly lower exhaled amount and higher thoracic nicotine delivery with nicotine salt form vs free-base. Considering body temperature and humidity also showed significant enhancement in nicotine delivery, so it is essential to account for biorelevant experimental conditions in benchtop testing.

Establishing quantitative relationships between changes in nasal spray in vitro metrics and drug delivery to the posterior nasal region.

Nasal sprays are typically characterized using in vitro spray metrics such as spray cone angle and droplet size distribution. It is currently not clear how these in vitro metrics correlate with regional nasal deposition, and these relationships could help explain the impact of product differences. In this study, the effects of changes in spray cone angle, spray velocity, spray ovality and droplet size distribution on regional nasal deposition were analyzed using a validated computational fluid dynamics model in recently developed adult characteristic nasal airway anatomies. The impact of the spray on the surrounding air phase was included. Results indicated that changes in spray cone angle largely influenced the nasal posterior deposition (PD) of the drug. Changes in the plume ovality and characteristic droplet size moderately influenced PD, but the results were dependent on the insertion conditions and nasal geometry. Changes in spray velocity and uniformity constant of the droplet size distribution had only minimal influence on PD. The rank order of metrics having the greatest to least impact on PD was cone angle ≫ plume ovality ≫ characteristic droplet size ≫ velocity ≫ size distribution uniformity constant. Overall, results from this study established quantitative relationships for predicting expected changes in PD.

In Vitro Comparison of Local Nasal Vaccine Delivery and Correlation with Device Spray Performance.

PURPOSE: This study is the first vaccine candidate in vitro investigation with a focus on finding a correlation between the spray characteristics and the delivery efficiency of the local deposition in the nasal airways of infants under 24 months using various intranasal devices. METHODS: In vitro tests were developed to measure the spray characteristics of four intranasal delivery devices and how they regionally deliver a candidate vaccine formulation matrix in five nasal airway replicas (3 to 24 months). The correlation between the spray performance, geometric parameters, and delivery efficiency were assessed. RESULTS: All four devices performed consistently in terms of spray characteristics and were capable of delivering a high percentage of the candidate vaccine to the target areas, with a minimum delivery efficiency of 80%. Moreover, the delivery efficiency was affected by either the spray droplet size distribution or the distance between the nozzle tip and the internal nasal valve. Correlations between the spray performance and the in vitro local dose deposition were established. CONCLUSION: The infant nasal model tests can be complementary to device spray performance evaluation. In the absence of in vivo correlations, they can also facilitate the process of new product development by estimating delivery a priori.

Anatomically realistic nasal replicas capturing the range of nasal spray drug delivery in adults.

To improve the relationships between commonly conducted in vitro studies for locally-acting nasal spray drug products with in vivo regional deposition, this study developed a set of in vitro adult nasal geometries that captured the range of nasal drug delivery to the region posterior to internal nasal valve (INV), also known as posterior delivery (PD), and evaluated their performance with existing in vivo data. The PD of fluticasone propionate (FP) and fluticasone furoate (FF) in 40 nasal cavities was statistically analyzed to identify three airway models representing the low, mean, and high PD in adults. The models were also externally validated by comparing the in vitro nasal deposition from a different drug product (mometasone furoate (MF)) with the relevant in vivo data. The three selected geometries represented the low, mean, and high PD with multiple nasal sprays. They were verified in terms of reproducibility of in vitro data and validated by showing a reasonable agreement with preexisting in vivo MF PD despite differences in administration and defining the regions. The three models are envisioned to potentially facilitate the development of locally-acting nasal sprays and provide a better understanding of how in vitro metrics relate to in vivo regional nasal deposition.

Importance of Spray-Wall Interaction and Post-Deposition Liquid Motion in the Transport and Delivery of Pharmaceutical Nasal Sprays.

Nasal sprays, which produce relatively large pharmaceutical droplets and have high momentum, are primarily used to deliver locally acting drugs to the nasal mucosa. Depending on spray pump administration conditions and insertion angles, nasal sprays may interact with the nasal surface in ways that creates complex droplet-wall interactions followed by significant liquid motion after initial wall contact. Additionally, liquid motion can occur after deposition as the spray liquid moves in bulk along the nasal surface. It is difficult or impossible to capture these conditions with commonly used computational fluid dynamics (CFD) models of spray droplet transport that typically employ a deposit-on-touch boundary condition. Hence, an updated CFD framework with a new spray-wall interaction (SWI) model in tandem with a post-deposition liquid motion (PDLM) model was developed and applied to evaluate nasal spray delivery for Flonase and Flonase Sensimist products. For both nasal spray products, CFD revealed significant effects of the spray momentum on surface liquid motion, as well as motion of the surface film due to airflow generated shear stress and gravity. With Flonase, these factors substantially influenced the final resting place of the liquid. For Flonase Sensimist, anterior and posterior liquid movements were approximately balanced over time. As a result, comparisons with concurrent in vitro experimental results were substantially improved for Flonase compared with the traditional deposit-on-touch boundary condition. The new SWI-PDLM model highlights the dynamicenvironment that occurs when a nasal spray interacts with a nasal wall surface and can be used to better understand the delivery of current nasal spray products as well as to develop new nasal drug delivery strategies with improved regional targeting.

Use of Airway Replicas in Lung Delivery Applications.

The use of extrathoracic airway replicas in optimization of drug delivery to the lungs with nebulizers, dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs) is discussed. Such airway replicas have been useful in evaluating new pulmonary drug delivery platforms mainly based on the comparison of the total lung dose (TLD) and the aerodynamic particle size distribution (APSD) of the aerosol distal to the physical models. The ability of these in vitro methods to replicate in vivo results has allowed advancements in respiratory drug delivery and in the accuracy and utility of in vitro-in vivo correlations (IVIVCs).

Evaluation of Intranasal Vaccine Delivery Using Anatomical Replicas of Infant Nasal Airways.

PURPOSE: Nasal delivery is a favorable route for vaccination against most respiratory infections, as antigen deposited in the nasal turbinate and Waldeyer's ring areas induce mucosal and systemic immune responses. However, little is known about the nasal distribution of the vaccines, specifically for infants. METHODS: Anatomical nasal replicas of five subjects, 3-24 months, were developed to assess local intranasal vaccine delivery using MAD Nasal™ device, and understand impact of breathing conditions and administration parameters. High performance liquid chromatography was used to quantify the deposition pattern and determine the delivery efficiency. RESULTS: The delivery efficiency on average for all models was found to be 86.57±14.23%. There were no significant differences in the total delivery efficiency between the models in all cases. However, the regional deposition pattern was altered based on the model and subsequent administration. Furthermore, removing the foam tip from the MAD Nasal™ device, to study the impact of insertion length, did not significantly increase the efficiency within the two models tested, 5- and 16-month. CONCLUSION: Incorporating nasal replicas in testing provided a benchmark to determine the efficiency of a common intranasal vaccine delivery combination product. This proposed platform would allow comparing other potential nasal vaccine delivery devices.

Correlations to Estimate the Key Anatomical Dimensions of Pediatric Nasal Airways using Minimally Invasive Measurements of Intranasal Pressure Gradient.

Background: Understanding the morphology of nasal airways is important in determining the nasal airway deposition of inhaled aerosol. Moreover, objective assessment of the anatomy of human nasal airways is useful to develop a database of reference or normal values as a resource to investigate anatomical abnormalities of airways. Current methods for the objective assessment of the nasal airways are either limited to very few dimensions or can only be performed by specialized researchers. Thus, the main objective of this study was to determine the correlations between the intranasal pressure gradient (Δp) and the key anatomical dimensions of the pediatric nasal airways, which could in turn allow the extrapolation of nasal airway morphology based on simple minimally invasive measurements of pressure. Methods: The anatomical data and Δp were obtained from in vitro studies with nasal airway models of 11 infants ages 3-18 months and 13 children ages 4-14 years old. Key anatomical dimensions were identified based on both rhinology and aerosol dosimetry literature. These anatomic data, including the volume, V, surface area, As, length, L, and the minimum cross-sectional area of the replicas, Amin, were then analyzed for correlation with Δp and flow parameters, using Bernoulli's principle and dimensional analysis. Results: Strong correlations were found between Δp and As/L for children, and between Δp and V/As for infants. Additional pressure gradient correlations were developed with Amin, V/As, V∕L, and L. Conclusions: The correlations identified between anatomic data and Δp have clinical implications in pediatric rhinology, suggesting that certain aspects of airway anatomy in infants and children can be predicted through the measurement of Δp. The airway dimensions, predicted using Δp measurement, may be used in tandem with aerosol nasal deposition correlations that account for nasal airway dimensions.

In vitro evaluation of regional nasal drug delivery using multiple anatomical nasal replicas of adult human subjects and two nasal sprays.

Quantifying drug delivery to the site of action using locally-acting nasal suspension sprays is a challenging but important step toward understanding bioequivalence (BE) between test and reference products. The main objective of this study was to investigate the in vitro deposition pattern of two common but different locally-acting nasal suspension sprays using multiple nasal cavities. Twenty anatomically accurate nasal replicas were developed from high-resolution sinonasal computed tomography scans of adults with healthy nasal airways. The airways were segmented into two regions of anterior and posterior to the internal nasal valve. Both sides of the septum were considered separately; hence, 40 nasal cavities were studied. The positioning of the spray nozzle in all 40 cavities was characterized by the head angle, coronal angle, and the insertion depth. Despite using a controlled protocol to minimize the anterior losses, a wide range of variability in posterior drug delivery was observed. The observed intersubject variability using this in vitro method may have important implications for understanding BE of locally-acting nasal suspension sprays.

Use of anatomically-accurate 3-dimensional nasal airway models of adult human subjects in a novel methodology to identify and evaluate the internal nasal valve.

The optimal method for radiographic evaluation of the internal nasal valve (INV) has not been established. The objective of this study was to develop a method to assess the cross-sectional area and the angle of the INV using anatomically-accurate 3D digital nasal airway models. Axial CT images of the paranasal sinuses of twenty adult subjects with healthy nasal airways (50% female and 50% age ≥ 50) were used to create the models. Patients with significant radiographic evidence of sinonasal disease were excluded. A primary cutting plane that passed through the edge of the nasal bone, upper lateral cartilage, and the head of the inferior turbinate was defined in coronal view. This primary coronal cutting plane was then rotated in 5° increments anteriorly while ensuring the anatomic criteria for the INV were still met. The cutting plane resulting in the minimum INV area was identified as the optimal cutting plane and the total cross-sectional area of INV in this plane,198.79 ± 54.57 mm2, was significantly less than the areas obtained using the existing methods for radiographic evaluation of the INV. The angle between the optimal cutting plane and nasal dorsum was 75.00 ± 10.26°, and the corresponding INV angle was 10.77 ± 6.02°.

Nicotine forms: why and how do they matter in nicotine delivery from electronic cigarettes?

INTRODUCTION: Unregulated e-cigarette devices and their nicotine content have amplified the potential of e-cigarettes as addictive agents. Several e-cigarette-related parameters have been identified altering nicotine's absorption profile, so their potential effects on addiction should be considered. Of these factors, nicotine forms (protonated and free base) play a significant role in the addiction potential yet their impact on nicotine's absorption has been studied with limited research. AREAS COVERED: Current review aims to emphasize on the possible mechanism behind different absorption profiles of nicotine forms considering their physical states (droplet and vapor phase) and the aerosol particle size, their analysis in e-cigarette research and the regulatory attention warranted by them to combat nicotine addiction in the population due to e-cigarettes. EXPERT OPINION: The protonated form of nicotine is being correlated with the smooth sensory effects and high nicotine absorption as compared to free base nicotine. With the introduction of nicotine salts, which yield mostly the protonated form, the youth popularity of e-cigarettes has spiked exponentially. While it is important to control nicotine levels in e-cigarette products, attention should also be given to the nicotine forms present in these products in order to address nicotine addiction in the population.

Mechanistic Understanding of High Flow Nasal Cannula Therapy and Pressure Support with an In Vitro Infant Model.

Despite the increased use of high flow nasal cannula therapy, little has been done to predict airway pressures for a full breath cycle. A 3-month-old infant in vitro model was developed, which included the entire upper airway and the first three bifurcations of the lungs. A breathing simulator was used to create a realistic breath pattern, and high flow was provided using a Vapotherm unit. Four cannulas of varying sizes were used to assess the effects of the inner diameter and nasal occlusion of the cannulas on airway pressures. At 8 L min-1, end expiratory pressures of 0.821-1.306 cm H2O and 0.828-1.133 cm H2O were produced in the nasopharynx and trachea, respectively. Correlations were developed to predict full breath cycle airway pressures, based on the gas flow rate delivered, cannula dimensions, as well as the breathing flow rate, for the nasopharynx and trachea. Pearson correlation coefficients for the nasopharynx and trachea correlations were 0.991 and 0.992, respectively. The developed correlations could be used to determine the flow rate necessary for a cannula to produce pressures similar to CPAP settings. The proposed correlations accurately predict the regional airway pressure up to and including 7 cm H2O of support for the entire breath cycle.

In Vitro Measurement of Regional Nasal Drug Delivery with Flonase,® Flonase® Sensimist,™ and MAD Nasal™ in Anatomically Correct Nasal Airway Replicas of Pediatric and Adult Human Subjects.

Background: The majority of current nasal delivery devices, commercialized for children, are developed for adults. Differences in the dose reaching the target are expected due to significant differences between the pediatric and adult nasal airway geometries and their inhalation patterns. This study aims to compare the efficacy of most common nasal drug delivery devices in terms of regional delivery of suspension and solution formulations in pediatric and adult subjects. Methods: Anatomically correct nasal models of 2-, 5-, and 50-year old subjects were developed to evaluate regional nasal delivery of suspensions of fluticasone propionate and fluticasone furoate delivered with Flonase® and Flonase® Sensimist™, respectively, and the delivery of an aqueous solution of a model drug, administered with MAD Nasal™. Relevant inhalation patterns were considered for each nasal airway geometry. Controlled administration methods were used, and all contributing parameters, including particle size, velocity, and plume geometry, are reported. Results: Regional deposition patterns resulting from Flonase® Sensimist™ and Flonase® were not significantly different in each replica (p > 0.05), despite their different plume geometry and droplet size distributions. However, there was a significant difference in deposition of nasal sprays between the pediatric (2- and 5-year old) and adult models (p < 0.05), while no statistical differences were found between the two pediatric models (p > 0.05). The MAD atomizer resulted in different deposition patterns in all three subjects (p < 0.05). Conclusion: Nasal sprays are not adequate delivery devices for pediatric population, due to the narrower nasal passage and greater anterior deposition (∼60%). MAD atomizer resulted in significantly less anterior deposition (∼10%-15%) compared to the nasal pumps, but there was ∼30% run off to the throat. An in vitro platform incorporating anatomically correct nasal geometries and inhalation patterns can guide the development of age-appropriate nasal drug delivery devices.

An in vitro evaluation of importance of airway anatomy in sub-regional nasal and paranasal drug delivery with nebulizers using three different anatomical nasal airway replicas of 2-, 5- and 50-Year old human subjects.

Intranasal delivery of nebulized drugs with the consideration of the nasal anatomy is not adequately studied. The objective of this study was to evaluate nasal and paranasal drug delivery with nebulizers, with and without pulsating airflow, in three anatomically-different nasal models in different age groups, considering normal and bidirectional breathing techniques. Anatomically-accurate nasal models of 2-, 5-, and 50-year old subjects were developed and tested to quantify sub-regional deposition of an aqueous solution of a model drug, nebulized with PARI SinuStar™ and Sinus™ nebulizers. Paranasal delivery was significantly enhanced using pulsating nebulization under bidirectional breathing administration technique for all subjects (p < 0.05). Airway morphology resulted in significantly different drug delivery efficiency (p < 0.05). Use of a modified nasal adaptor enhanced the inhaled dose and resulted in significantly higher percent recovery, 68.41±13.56%, compared to the standard design,10.35±1.75%. In the adult subject, paranasal delivery was equal to 19.34±1.21%, and 5.99±0.95% using PARI Sinus™ nebulizer, with and without pulsating airflow, respectively. In the pediatric subjects, pulsating paranasal delivery was 12.80±0.28%, but without pulsating airflow no drug reached the target. This study confirmed that bidirectional breathing and pulsating airflow are beneficial for improved paranasal aerosol delivery in children similar to previous findings for adults.

Intranasal Filtration of Inhaled Aerosol in Human Subjects as a Function of Nasal Pressure Drop.

BACKGROUND: Intersubject variability in nasal deposition of inhaled aerosol is significant because of the differences in nasal anatomy and breathing rate. The notable limitation of the majority of previously developed predictive correlations is including a limited number of subjects. A few recent studies have considered a wide age range of subjects, but the resulting correlations require the knowledge of the dimensions of the nasal airways and the properties of inhaled gas. In this study empirical correlations are proposed to predict aerosol deposition in nasal airways of subjects of different age as a function of intranasal pressure drop and the particle aerodynamic diameter. METHODS: The experimental nasal deposition and pressure drop data in anatomically correct nasal replicas of 5 adults, 13 children aged 4-14 years, and 11 infants aged 3-18 months were reanalyzed. The range of aerodynamic diameter was 0.5-5.3 µm and physiological breathing at different activity levels was considered. Correlations between nasal deposition and a deposition parameter including the aerodynamic size of inhaled aerosol and nasal pressure drop were developed with nonlinear least-square algorithms. The general coefficient of determination r2 was used to evaluate the fitting accuracy for each correlation. RESULTS: New correlations were developed to predict the intranasal deposition of particles as a function of intranasal pressure drop and particle size for pediatric and adult subjects. The intranasal deposition fraction in adults and children can be calculated using the same correlation, whereas the intranasal deposition in infants followed a different trend line because of higher intranasal pressure drop in infants. CONCLUSION: This study was the first offering correlations to predict intranasal deposition in multiple age groups using only the aerodynamic size of inhaled aerosol and nasal pressure drop. These correlations include the effects of intersubject variability in nasal deposition within each age group and among different age groups.

Advanced testing method to evaluate the performance of respirator filter media.

Filter media for respirator applications are typically exposed to the cyclic flow condition, which is different from the constant flow condition adopted in filter testing standards. To understand the real performance of respirator filter media in the field it is required to investigate the penetration of particles through respirator filters under cyclic flow conditions representing breathing flow patterns of human beings. This article reports a new testing method for studying the individual effect of breathing frequency (BF) and peak inhalation flow rate (PIFR) on the particle penetration through respirator filter media. The new method includes the use of DMA (Differential Mobility Analyzer)-classified particles having the most penetrating particle size, MPPS (at the constant flowrate of equivalent mean inhalation flow rate, MIFR) as test aerosol. Two condensation particle counters (CPCs) are applied to measure the particle concentrations at the upstream and downstream of test filter media at the same time. Given the 10 Hz sampling time of CPCs, close-to-instantaneous particle penetration could be measured. A pilot study was performed to demonstrate the new testing method. It is found that the effect of BF on the particle penetration of test respirator filter media is of importance at all the tested peak inhalation flow rates (PIFRs), which is different from those reported in the previous work.

Production of Highly Charged Pharmaceutical Aerosols Using a New Aerosol Induction Charger.

PURPOSE: Properly charged particles can be used for effective lung targeting of pharmaceutical aerosols. The objective of this study was to characterize the performance of a new induction charger that operates with a mesh nebulizer for the production of highly charged submicrometer aerosols to bypass the mouth-throat and deliver clinically relevant doses of medications to the lungs. METHODS: Variables of interest included combinations of model drug (albuterol sulfate) and charging excipient (NaCl) as well as strength of the charging field (1-5 kV/cm). Aerosol charge and size were measured using a modified electrical low pressure impactor system combined with high performance liquid chromatography. RESULTS: At the approximate mass median aerodynamic diameter (MMAD) of the aerosol (~0.4 µm), the induction charge on the particles was an order of magnitude above the field and diffusion charge limit. The nebulization rate was 439.3 ± 42.9 µl/min, which with a 0.1% w/v solution delivered 419.5 ± 34.2 µg of medication per minute. A new correlation was developed to predict particle charge produced by the induction charger. CONCLUSIONS: The combination of the aerosol induction charger and predictive correlations will allow for the practical generation and control of charged submicrometer aerosols for targeting deposition within the lungs.