Total Lung Deposition Research Articles

Validation of Radiolabeling of Drug Formulations for Aerosol Deposition Assessment of Orally Inhaled Products

Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man.

Exposure assessment and associated lung deposition calculations for vehicular exhaust in four metropolitan cities of Pakistan

Ambient aerosol concentrations along the roadside of metropolitan cities of Pakistan were measured using a Grimm 1.109 dust monitor. Considering the high ambient aerosol concentrations, regional lung deposition of aerosol particles in the human respiratory tract was calculated to assess extent of exposure. Lung deposition was computed in terms of mass concentration and the associated surface area for 12 male traffic wardens using the latest version of the stochastic lung deposition code Inhalation, Deposition, and Exhalation of Aerosols in the Lung. The results have revealed 4 to 10 times higher concentrations than recommended by WHO guidelines. The deposition results derived from the model disclose that extrathoracic deposition is in the range of 22 to 28 % with total lung deposition ranging from 40 to 44 % for the scanned particle window of 0.25-10 μm. Considering an average 8-h shift per day and an average breathing rate of 1.3 m(3) h(-1), it is approximated that in a worker, up to 1.6 mg of inhalable particle mass can deposit per day.

In VitroTests for Aerosol Deposition II: IVIVCs for Different Dry Powder Inhalers in Normal Adults

A new in vitro test method for dry powder inhalers (DPIs) was recently found to be predictive of the published in vivo results for Budelin Novolizer. The present study was intended to assess the method's robustness by evaluating correlations between average drug deposition in vitro and in vivo from five different DPIs. In vitro drug deposition from five marketed DPIs was assessed in a realistic physical airway model of a "medium" sized adult in an experimental setup that allowed deposition to be characterized regionally for carefully selected simulated air flow rate versus time profiles. The DPIs studied were Spiriva(®) HandiHaler(®), Relenza(®) Diskhaler(®), Salbutamol Easyhaler(®), Pulmicort(®) Turbuhaler(®), and Foradil(®) Aerolizer(®). In vitro regional deposition results were compared with those reported in the literature in order to create in vitro-in vivo correlations (IVIVCs) for each inhaler. Mean percent total lung deposition (TLD ± SD) in vitro for Spiriva HandiHaler, Relenza Diskhaler, Salbutamol Easyhaler, Pulmicort Turbuhaler, and Foradil Aerolizer were 17.3 ± 1.2, 22.6 ± 1.1, 29.0 ± 1.1, 28.0 ± 3.0, and 21.7 ± 1.2, respectively. These results showed excellent agreement with reported in vivo values, with absolute prediction errors in TLD of ≤ 2% for all DPIs except Relenza Diskhaler. Similarly, in vitro mouth-throat and device deposition results were stoichiometrically comparable to those reported in vivo for all DPIs except Relenza Diskhaler and Turbuhaler. Inspection of the scintigraphy studies for Relenza Diskhaler and Turbohaler revealed possible problems with powder labeling and result interpretation in their in vivo clinical assessments. A characteristic physical airway model representing a medium-sized adult, when coupled to carefully chosen characteristic inhalation maneuvers used in the clinic, produced results that correlated with regional drug deposition estimates from scintigraphy across a group of different DPIs.

Development of Budesonide Nanocluster Dry Powder Aerosols: Formulation and Stability

The physical and chemical stability of dry powder aerosol formulations is an essential component in the development of an inhaled therapeutic. The pharmaceutical processing methods and storage conditions are primary determinants of the stability of a dry powder inhaler (DPI) formulation. Wet milling was used to produce budesonide NanoClusters (NCs), which are agglomerates of drug nanoparticles (≈ 300 nm) with a mean aerodynamic diameter between 1 and 3 µm, capable of deep lung penetration. In this study, the reproducibility of NC processing and performance was established. The physical stability of a selected budesonide NC formulation was investigated using industry standard dose content uniformity and cascade impaction techniques. The chemical stability of the lead formulation was also determined as a function of processing parameters and storage conditions. This study confirms the reproducibility and robust stability of NC powders as a novel means to turn drug particles into high-performance aerosols.

Aerosol deposition in health and disease.

The success of inhalation therapy is not only dependent upon the pharmacology of the drugs being inhaled but also upon the site and extent of deposition in the respiratory tract. This article reviews the main mechanisms affecting the transport and deposition of inhaled aerosol in the human lung. Aerosol deposition in both the healthy and diseased lung is described mainly based on the results of human studies using nonimaging techniques. This is followed by a discussion of the effect of flow regime on aerosol deposition. Finally, the link between therapeutic effects of inhaled drugs and their deposition pattern is briefly addressed. Data show that total lung deposition is a poor predictor of clinical outcome, and that regional deposition needs to be assessed to predict therapeutic effectiveness. Indeed, spatial distribution of deposited particles and, as a consequence, drug efficiency is strongly affected by particle size. Large particles (>6 μm) tend to mainly deposit in the upper airway, limiting the amount of drugs that can be delivered to the lung. Small particles (<2 μm) deposit mainly in the alveolar region and are probably the most apt to act systemically, whereas the particle in the size range 2-6 μm are be best suited to treat the central and small airways.

Understanding Penetration Index Measurements and Regional Lung Targeting

Radiolabeling of pharmaceutical inhalation aerosols began in the late 1970s. Since then, well over 100 studies have been published. These studies have documented lung deposition for all inhalation dosage forms; pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), soft mist inhalers (SMIs), and nebulizers. They have provided valuable insight into the factors that influence total and regional lung deposition. Taken globally, this collection of data has recently been used to elucidate the influence of intersubject variability in head geometry on total lung deposition, showing good correspondence between theory and experiment. The analysis reported here is an attempt to take this data set one step "deeper" into the airways and understand the relationship between P/C ratio, derived from 2D imaging, and a more anatomically relevant biological distribution within the lung, 24-h clearance. Intersubject variability in regional deposition is also analyzed, although due to the sparse nature of the reported individual data only tentative conclusions can be drawn. Many different techniques for derivation and analysis of scintigraphic data have been reported in the literature, and this leads to some difficulties when performing the "meta-analyses" reported below. In this regard it is recommended that standardization of scintigraphy techniques should be a future goal.

In VitroTests for Aerosol Deposition. I: Scaling a Physical Model of the Upper Airways to Predict Drug Deposition Variation in Normal Humans

In vitro-in vivo correlations (IVIVCs) are needed to relate in vitro test results for deposition to mean data from clinical trials, as well as the extremes in a population. Because drug deposition variations are related to differences in airway dimensions and inhalation profiles, this article describes the development and validation of models and methods to predict in vivo results. Three physical models of the upper airways were designed as small, medium, and large versions to represent 95% of the normal adult human population. The physical dimensions were validated by reference to anatomy literature. The models were constructed by rapid prototyping, housed in an artificial thorax, and used for in vitro testing of drug deposition from 200 μg Budelin Novolizers using a breath simulator to mimic the inhalation profiles used in the clinic. In vitro results were compared to those reported in vivo. The "average" model was scaled to produce "small" and "large" versions by multiplying linear dimensions by 0.748 or 1.165, respectively, based on reports of the mean and standard deviation of airway volume across a normal adult population. In vitro deposition variation under fixed test conditions was small. Testing in the model triplet however, using air flow rate versus time profiles based on the mean and the extremes reported in the clinic, produced results for total lung deposition (TLD) in vitro consistent with the complete range of drug deposition results reported in vivo. The effects of variables such as flow rate in vitro were also predictive of in vivo deposition. A new in vitro test method is described to predict the median and range of aerosol drug deposition seen in vivo. The method produced an IVIVC that was consistent with 1:1 predictions of total lung deposition from a marketed powder inhaler in trained normal adults.

Development of nano alpha-ketoglutarate nebulization formulation and its pharmacokinetic and safety evaluation in healthy human volunteers for cyanide poisoning

Development of nano alpha-ketoglutarate (A-KG) nebulization formulation for neutralization of inhaled cyanide ion toxicity. Objectives of the present study were to (a) develop a novel A-KG nebulization formulation against cyanide poisoning, particularly hydrogen cyanide gas (b) validate its respiratory fraction in vitro and in vivo, and (c) create its pharmacokinetic data in human volunteers. The formulation was optimized on the basis of particle size of aerosolized droplets after nebulization in 6 volunteers. Gamma scintigraphy was used to quantify total and regional lung deposition of nebulized A-KG after radiolabeling it with Technetium-99m. The formulation was optimized using 30% ethanol–saline with particle size in the range of 300–500 nm. In vitro and in vivo studies showed that drug nebulization resulted in a significant respirable fraction of 65 ± 0.6% with whole lung deposition of 13 ± 1%. Human pharmacokinetic data was derived in 6 healthy human volunteers with peak serum concentration ( C max) of 39 ± 3 μg/ml, while the area under curve (AUC) after inhalation was 376 ± 23 μg × h/ml indicating that the drug was rapidly and completely absorbed when targeted directly to lungs. Significant lung deposition of A-KG was achieved with the developed formulation. The formulation appears to have several advantages, including the potential of neutralizing inhaled CN − ions in the lungs themselves. It is a safe and efficacious procedure, suitable for hospital or ambulance use in accidental cyanide poisoning cases, or as a preventive approach for fire-rescue teams.

Introduction 1000 Years of Pharmaceutical Aerosols: What Remains to Be Done?

Introduction 1000 Years of Pharmaceutical Aerosols: What Remains to Be Done?

New asthma drugs: small molecule inhaled corticosteroids

Small-particle inhaled corticosteroid (ICS) metered-dose inhalers were recently developed to treat asthma as part of the CFC to HFA propellant switch mandated by the Montreal Protocol. Two such ICS, beclomethasone dipropionate (BDP) and ciclesonide (CIC), are available in the United States and are formulated in HFA solutions. A major advantage of small-particle ICS is that they have improved total lung deposition and consequently, effective asthma control is achieved at lower daily doses than the large-particle ICS. Another advantage of small-particle ICS is that they are able to reach the small airways and consequently, may result in increased efficacy. Indeed, recent studies have demonstrated the effect of small-particle ICS on asthmatic inflammation in the small airways. Another advantage of small-particle ICS is that they may have an improved safety profile. Small-particle inhalers generally deposit decreased amounts of drug in the oropharynx than their CFC counterparts possibly resulting in a lower incidence of oropharyngeal candidiasis. However, growth studies and most HPA studies do not support improved safety on the basis of particle size alone and some studies suggest even higher systemic bioavailability and safety risk with smaller particles, depending on the molecule and the formulation. Further efficacy and safety studies are clearly warranted to determine any potential advantages of small-particle ICS, particularly in long-term disease modification where large-particle ICS have failed, and in infants and pre-schoolers, in whom airway delivery is problematic with current formulations.

Deposition of Albuterol Aerosol Generated by Pneumatic Nebulizer in the Sophia Anatomical Infant Nose-Throat (SAINT) Model

To quantify distribution of albuterol aerosol generated by a pneumatic nebulizer within the nose and lungs of a model of a 9-month-old child (SAINT) and aerosol loss to the environment, during simulated breathing at increasing tidal volumes (TVs). (99m)technetium-labeled albuterol aerosol was generated by an IPI nebulizer with face-mask. Deposition was quantified as a percentage of emitted dose using gamma scintigraphy. Lung deposition was similar for all TVs, averaging 7.17 +/- 0.01%, 9.34 +/- 0.01% and 9.41 +/- 0.02% at 50, 100 and 200 mL TV, respectively. In contrast, nose deposition increased significantly with TV, averaging 4.40 +/- 0.02%, 11.39 +/- 0.02% and 22.12 +/- 0.02% at 50 mL, 100 mL and 200 mL TV, respectively (all p < 0.0167). Aerosol loss to the environment was significantly lower at 200 mL TV (53.81 +/- 0.04%), compared to 50 mL (71.99 +/- 0.02%) (p < 0.0167). Our results suggest that nasal deposition of albuterol aerosol generated by a pneumatic nebulizer in 9-month-old infants may be significantly affected by changes in TV, ranging between 50 to 200 mL, whereas total lung deposition may not be affected. These results also predict that environmental losses would be highest when administering to a child breathing at 50 mL TV. These data should be useful to companies who are working to improve aerosol delivery systems to treat infants.

Pulmonary Targeting of Nanoparticle Drug Matrices

Nanoparticle drug matrices using lipids or liposomes, with diameters of 40-300 nm, have recently been developed to encapsulate drugs like Insulin, Budesonide, and Rifampicin for pulmonary delivery raising interest in their regional lung deposition. Lung deposition has so far been modeled using a one-dimensional transport equation, with or without moving airway boundaries, and a lumped deposition term for particle diffusion, sedimentation, and impaction. Here, a two-dimensional transport model has been developed with an explicit treatment of radial diffusion, the primary mechanism for nanoparticle deposition. Regional lung deposition was calculated using Weibel's whole lung model geometry during normal breathing and medical inhalation cycles. Model predictions agree well with measurements of total and pulmonary lung deposition for particles of 10 nm to 10 μm, with earlier models incorporating moving boundaries and aerosol dynamics, and with the reported regional lung deposition of inhaled dry powder insulin. To simulate medical inhalation, the model was run with inhalation times from 2-6 sec and breath hold from 0-10 sec. A high and relatively invariant pulmonary deposition fraction between 70 and 95% was predicted for a broad nanoparticle size range (50-200 nm) for inhalation cycles with breathing rate between 500 and 2000 cm(3) sec(-1) and breath hold of 5-10 sec. Thus, nanoparticles may be able to deliver consistent lung doses, over modest breath hold periods, even with intrapatient variability in breathing rate. A linearized nomogram was provided as a heuristic for design of nanoparticle drug matrices to target the pulmonary lung.

Aerosol delivery of nebulised budesonide in young children with asthma

Lung deposition of inhaled steroids, likely to be of benefit in the anti-inflammatory treatment of asthma in young children, is low. This is explained by age specific anatomical and physiological characteristics as well as poor cooperation with aerosol therapy. However, total lung deposition and the ratio of lung deposition to oropharyngeal deposition are key determinants of clinical efficacy and of systemic side effects of aerosolized drugs. The aim of this study was to determine lung deposition and ratio of lung deposition to oropharyngeal deposition using a modified vibrating membrane nebuliser to deliver budesonide with a small particle size, taking into account the needs of young children. Ten asthmatic children (5 males), mean age 20.3 months (range 6-41 months) inhaled radiolabelled budesonide (MMD 2.6microm) through a modified vibrating membrane nebuliser (modified PARI e-Flow). Lung deposition expressed as a percentage of the emitted dose was measured using scintigraphy and the ratio of lung deposition to oropharyngeal deposition was calculated. Mean lung deposition (SD) expressed as percentage of emitted dose and mean lung to oropharyngeal deposition ratio (SD) in quietly breathing children (n=5) and in children crying during inhalation were 48.6% (10.5) versus 20.0% (10.9), and 1.0 (0.3) versus 0.3 (0.2), respectively. We have shown that by using an improved age-adjusted complementary combination of delivery device and drug formulation to deliver small particles, lung deposition and ratio of lung deposition to oropharyngeal deposition in young asthmatic children is highly improved. But the main factor limiting aerosol delivery in this age group remains cooperation.

A Gamma Scintigraphy Study to Investigate Lung Deposition and Clearance of Inhaled Amikacin-Loaded Liposomes in Healthy Male Volunteers

The purpose of this study was to investigate the inhalation of a liposomal formulation of amikacin in healthy male volunteers in terms of pulmonary deposition, clearance, and safety following nebulization with a commercial jet nebulizer. Amikacin was encapsulated in liposomes comprised of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol via a proprietary manufacturing process (20 mg/mL final amikacin concentration). The liposomes were radiolabeled with (99m)Tc using the tin chloride labeling method. A nominal dose of 120 mg of drug product was loaded into a PARI LC STAR nebulizer, aerosolized using a PARI Boy compressor where subjects inhaled for 20 min. Lung deposition was determined by gamma scintigraphy in three healthy male volunteers at the following time points (0, 1, 3, 6, 12, 24, 48, and 72 h post-administration). Total lung deposition, expressed as a percentage of the emitted dose, was 32.3 +/- 3.4%. The time-dependent retention of radiolabeled liposomes was biphasic with an initial rapid reduction in counts, followed by a slower phase to 48 h. The overall mean retention at 24 and 48 h was 60.4 and 38.3% of the initial dose deposited, respectively. The observed clearance of radiolabel is consistent with clearance of amikacin following aerosol delivery to rats. There were no clinically significant changes in laboratory parameters, vital signs, or ECG. No adverse events including cough or bronchospasm were reported. Inhalation of a single nominal dose of 120 mg liposomal amikacin results in prolonged retention of drug-loaded liposomes in the lungs of healthy volunteers. The treatment was well tolerated.

Lung deposition of inhaled 1-proteinase inhibitor in cystic fibrosis and 1-antitrypsin deficiency

Individuals with alpha(1)-antitrypsin (AAT) deficiency and cystic fibrosis (CF) have a protease-antiprotease imbalance in their lungs, which leads to early onset progressive lung disease. Inhalation of AAT may restore protective levels in the lungs. This study aimed to determine the efficiency of delivering AAT using a novel inhalation device in subjects with AAT deficiency and CF compared with healthy subjects. In total, 20 subjects (six healthy, seven with AAT deficiency and seven with CF) inhaled approximately 70 mg of radiolabelled active AAT, with controlled breathing patterns adjusted to lung function. Post-inhalation, total and regional lung deposition and extrathoracic deposition of radiolabelled AAT were measured. Total lung deposition of AAT was approximately 70% of the filling dose. The magnitude of deposition was similar in all treatment groups, with no adverse effect on lung function or any influence of disease severity on total lung deposition. Inhalation with controlled breathing patterns using the AKITA(2) device (lung function adapted) leads to high total lung deposition regardless of the degree of lung function impairment. Delivery of large amounts of AAT was achieved in a short period of time. This device may be an ideal option for aerosol therapy.

Phospholipid-Induced In Vivo Particle Migration to Enhance Pulmonary Deposition

Amount of drug actually reaching the target region in the lung following pulmonary inhalation is often estimated at less than 10% for older devices. Current particle and device engineering technologies have improved on this but still fail to recover the "wasted" fraction of the drug and deliver it deeper into the lungs, which is generally desirable. FDA has approved several exogenous surfactants for prophylaxis and rescue treatment of respiratory distress syndrome (RDS). Their approved mode of administration (intratracheal instillation) and site of action (alveolar spaces) suggest that the phospholipids in the exogenous surfactants can spread from the trachea to alveolar air spaces and exert advantageous effects. We investigated whether in vivo lung migration of particles based on this phenomenon was possible and could be quantified based on changes in total and regional deposition of fluorescently labeled latex beads, utilized as an insoluble drug model. Following intranasal administration of beads, migration to rodent lungs was monitored upon intranasal instillation of Survanta (exogenous surfactant) or saline (control). After intranasal instillation approximately 12% of beads were found to migrate to the lung, and total lung deposition increased by approximately 10% on administration of Survanta or saline (control). After intranasal administration approximately 1% of beads in the lung were found to migrate to peripheral regions of the lungs, and a four- to six-fold increase in peripheral lung deposition was observed after Survanta instillation, compared to the saline control, which was determined to be independent of dose and volume of Survanta instillate in the range we studied. The in vivo rodent studies provided support for the idea that intranasally administered particles deposited in non-target lung locations may be translocated to peripheral sites in the lung therapeutically after surfactant application.

Nano-salbutamol dry powder inhalation: A new approach for treating broncho-constrictive conditions

Nanoparticle DPI is known to have deeper lung penetration but its clinical utility as a potentially better treatment option needs to be evaluated in the light of higher expected mucociliary movement of the nanoparticles compared to micronized DPI. The objective of this study was to make nano-salbutamol sulphate (SBS) DPI, radiolabel it with Tc-99m using a novel surface labeling methodology, characterize the formulation and assess its in vitro and in vivo deposition in healthy human volunteers to estimate its bioavailability in the target area. Nano-SBS with a mean particle of 60.71 ± 35.99 nm was produced using liquid anti-solvent precipitation method. The drug particles were spherical, pure and crystalline. Anderson cascade impaction showed that blend formulations of Nano-SBS exhibited significantly higher respirable fraction of 45.2% compared to the known behavior of micronized salbutamol sulphate blends. Though the particle size tended to increase due to solid phase interaction after blending with lactose, there was definitive correlation between the radiolabeled and non-radiolabeled forms. In 10 healthy volunteers, lower oropharyngeal depositions (25.3 ± 4.5%) were observed with nano-SBS formulation compared to micronized SBS formulation (58.4 ± 6.1%). Furthermore, Nano-SBS formulations showed nearly 2.3-fold increase in total lung deposition compared to micronized SBS. The in vivo deposition data and the ratio of peripheral to central lung deposition (P/C) of 1.12 ± 0.4 indicate that Nano-SBS is evenly distributed within different lung regions. As demonstrated for SBS, nano-sizing may enhance regional deposition and thus provide an attractive particle engineering option for the development of blend formulations for inhalation delivery.

Recent Advances in Predictive Understanding of Respiratory Tract Deposition

Accurate prediction of respiratory tract deposition is important in gauging the health risks of ambient bioaerosols and environmental aerosols, as well as in developing pharmaceutical aerosols for drug delivery. The present article highlights recent advances in the prediction of total, extrathoracic, and lung deposition fractions of inhaled aerosols over a broad range of parameters for both oral and nasal breathing. These advances build on recent data from in vivo and in vitro studies that have benefited from recent improvements in high-resolution imaging, rapid prototyping, and computational simulation abilities that have significantly enhanced the current understanding of respiratory tract deposition. It is anticipated that the relatively simple equations for predicting total or whole lung deposition that follow from the recent work discussed herein will allow for improved correlation between respiratory tract deposition and a wide range of health outcomes.

Pulmonary absorption of aerosolized fluorescent markers in the isolated rabbit lung

For the development of aerosolized controlled release formulations such as liposomes or nanoparticles, the use of suitable model drugs is necessary. This study compared the pulmonary absorption of the three structurally diverse fluorescent markers 5(6)-carboxyfluorescein (CF), 8-methoxypyrene-1,3,6-trisulfonic acid trisodium salt (MPTS) and rhodamine 6G (R6G) after nebulization in an isolated, perfused and ventilated rabbit lung. Aerosol particle size and lung deposition as well as lipophilicity of the fluorescent markers were determined. Dye concentrations were measured in the recirculating buffer and in the bronchoalveolar lavage. The MMAD of the dye aerosols ranged between 4.70 and 4.88 μm, total lung deposition was 0.40 ± 0.05 ml. The 1-octanol/water partition coefficient as measure for lipophilicity was −3.45 ± 0.16 for CF, −4.95 ± 0.21 for MPTS and 2.69 ± 0.18 for R6G. The perfusate concentration showed an increase to ∼400 ng/ml (53.4 ± 6.8% of the intrapulmonary deposited dye) for CF and ∼230 ng/ml (29.1 ± 2.0%) for MPTS, respectively; R6G concentration increased in the first 30 min to ∼38 ng/ml followed by a gradual decrease to ∼26 ng/ml (3.3 ± 0.7%). In conclusion, these data suggest that the hydrophilic dye CF is suitable to study drug transport from aerosolized controlled release formulations across the lung barrier. In contrast, the highly water-soluble fluorescent probe MPTS demonstrates insufficient recovery and the lipophilic R6G high accumulation in lung tissue.

Deposition of Ultrafine (NANO) Particles in the Human Lung

Increased production of industrial devices constructed with nanostructured materials raises the possibility of environmental and occupational human exposure with consequent adverse health effects. Ultrafine (nano) particles are suspected of having increased toxicity due to their size characteristics that serve as carrier transports. For this reason, it is critical to refine and improve existing deposition models in the nano-size range. A mathematical model of nanoparticle transport by airflow convection, axial diffusion, and convective mixing (dispersion) was developed in realistic stochastically generated asymmetric human lung geometries. The cross-sectional averaged convective-diffusion equation was solved analytically to find closed-form solutions for particle concentration and losses per lung airway. Airway losses were combined to find lobar, regional, and total lung deposition. Axial transport by diffusion and dispersion was found to have an effect on particle deposition. The primary impact was in the pulmonary region of the lung for particles larger than 10 nm in diameter. Particles below 10 nm in diameter were effectively removed from the inhaled air in the tracheobronchial region with little or no penetration into the pulmonary region. Significant variation in deposition was observed when different asymmetric lung geometries were used. Lobar deposition was found to be highest in the left lower lobe. Good agreement was found between predicted depositions of ultrafine (nano) particles with measurements in the literature. The approach used in the proposed model is recommended for more realistic assessment of regional deposition of diffusion-dominated particles in the lung, as it provides a means to more accurately relate exposure and dose to lung injury and other biological responses.