Mechanisms of Pharmaceutical Aerosol Deposition in the Respiratory Tract

Aerosol delivery is noninvasive and is effective in much lower doses than required for oral administration. Currently, there are several types of therapeutic aerosol delivery systems, including the pressurized metered-dose inhaler, the dry powder inhaler, the medical nebulizer, the solution mist inhaler, and the nasal sprays. Both oral and nasal inhalation routes are used for the delivery of therapeutic aerosols. Following inhalation therapy, only a fraction of the dose reaches the expected target area. Knowledge of the amount of drug actually deposited is essential in designing the delivery system or devices to optimize the delivery efficiency to the targeted region of the respiratory tract. Aerosol deposition mechanisms in the human respiratory tract have been well studied. Prediction of pharmaceutical aerosol deposition using established lung deposition models has limited success primarily because they underestimated oropharyngeal deposition. Recent studies of oropharyngeal deposition of several drug delivery systems identify other factors associated with the delivery system that dominates the transport and deposition of the oropharyngeal region. Computational fluid dynamic simulation of the aerosol transport and deposition in the respiratory tract has provided important insight into these processes. Investigation of nasal spray deposition mechanisms is also discussed.     

In vitro and in vivo aspects of cascade impactor tests and inhaler performance: A review

The purpose of this review is to discuss the roles of cascade impactor (CI) data in inhaler assessment and to examine the relationship between aerodynamic particle size distribution (APSD) and the clinical response to inhaled drugs. A systematic literature search of studies linking APSD to clinical response was undertaken. Two distinct roles for CI-generated data were identified: (1) the control of inhaler/drug product quality; and (2) the provision of data that may be predictive of particle deposition in the respiratory tract. Method robustness is required for the former application, combined with simplicity in operation, resulting in rudimentary attempts to mimic the anatomy of the respiratory tract. The latter necessitates making the apparatus and its operation more closely resemble patient use of the inhaler. A CI cannot perfectly simulate the respiratory tract, since it operates at constant flow rate, while the respiratory cycle has a varying flow-time profile. On the basis of a review of studies linking APSD to clinical response of inhaled drugs, it is concluded that attempts to use CI-generated data from quality control testing to compare products for bioequivalence are likely to have only limited success, as links between laboratory-measured APSD, particle deposition in the respiratory tract, and clinical response are not straightforward.     

Calculation of regional deposition of aerosol in the respiratory tract

The removal of air-borne particles in the respiratory tract is treated to enable regional deposition to be inferred from measurement of expired aerosol as well as predicted from theory of the primary removal processes. The analysis uses the analogy of a continuous tubular filter-bed and includes consideration of respiratory pauses and the mechanical mixing of gas flow. Derived equations relate regional deposition, distribution of aerosol in the expired air, and efficiency of removal at different depths in the respiratory tract.     

Effects of oral airway geometry characteristics on the diffusional deposition of inhaled nanoparticles

The deposition of ultrafine aerosols in the respiratory tract presents a significant health risk due to the increased cellular-level response that these particles may invoke. However, the effects of geometric simplifications on local and regional nanoparticle depositions remain unknown for the oral airway and throughout the respiratory tract. The objective of this study is to assess the effects of geometric simplifications on diffusional transport and deposition characteristics of inhaled ultrafine aerosols in models of the extrathoracic oral airway. A realistic model of the oral airway with the nasopharynx (NP) included has been constructed based on computed tomography scans of a healthy adult in conjunction with measurements reported in the literature. Three other geometries with descending degrees of physical realism were then constructed with successive geometric simplifications of the realistic model. A validated low Reynolds number k-omega turbulence model was employed to simulate laminar, transitional, and fully turbulent flow regimes for the transport of 1-200 nm particles. Results of this study indicate that the geometric simplifications considered did not significantly affect the total deposition efficiency or maximum local deposition enhancement of nanoparticles. However, particle transport dynamics and the underlying flow characteristics such as separation, turbulence intensity, and secondary motions did show an observable sensitivity to the geometric complexity. The orientation of the upper trachea was shown to be a major factor determining local deposition downstream of the glottis and should be retained in future models of the respiratory tract. In contrast, retaining the NP produced negligible variations in airway dynamics and could be excluded for predominantly oral breathing conditions. Results of this study corroborate the use of existing diffusion correlations based on a circular oral airway model. In comparison to previous studies, an improved correlation for the deposition of nanoparticles was developed based on a wider range of particle sizes and flow rates, which captures the dependence of the Sherwood number on both Reynolds and Schmidt numbers.     

Effect of altered G levels on deposition of particulates in the human respiratory tract.

The primary mode of depositon of particles in the respiratory tract in the size range 0.5-10 mum diam (unit density) is sedimentation. The rate of sedimentation is directly proportional to the velocity of settling of the particle. Therefore, the total deposition of particles in the respiratory tract as well as the region of deposition is affected by changes in gravity. Human subjects were exposed to aerosols of 2.02-mum-diam polyvinyltoluene particles at 0, 0.5, 1.0, and 2.0 G. Total deposition was measured at each G level. Results indicate an almost linear increase in total deposition with increasing G levels over the range studied. The deposition measured at 1 G was less than reported in earlier experiments and the deposition at levels less than 1 G was less than had been calculated by Muir and Beeckmans. These data show that although sedimentation plays the major role in depostion of 2.02 mum particles, it is less than previously described.     

Theoretical evaluation of aerosol deposition in anatomical models of mammalian lung airways

A computational model to predict deposition of a wide variety of particulate pollutants in several species of mammals is presented. The model incorporates breathing pattern and detailed anatomical models of the respiratory tract based on extensive morphometric measurements of individual airways. The predicted deposition from this general model is in close agreement with observed deposition of monodisperse aerosols in rats. Particle size and density and respiratory breathing patterns are the critical parameters affecting regional deposition.     

Characterization and Deposition of Respirable Large- and Small-Particle Bioaerosols

The deposition patterns of large-particle microbiological aerosols within the respiratory tract are not well characterized. A novel system (the flow-focusing aerosol generator [FFAG]) which enables the generation of large (>10-μm) aerosol particles containing microorganisms under laboratory conditions was characterized to permit determination of deposition profiles within the murine respiratory tract. Unlike other systems for generating large aerosol particles, the FFAG is compatible with microbiological containment and the inhalational challenge of animals. By use of entrapped Escherichia coli cells, Bacillus atrophaeus spores, or FluoSphere beads, the properties of aerosols generated by the FFAG were compared with the properties of aerosols generated using the commonly available Collison nebulizer, which preferentially generates small (1- to 3-μm) aerosol particles. More entrapped particulates (15.9- to 19.2-fold) were incorporated into 9- to 17-μm particles generated by the FFAG than by the Collison nebulizer. The 1- to 3-μm particles generated by the Collison nebulizer were more likely to contain a particulate than those generated by the FFAG. E. coli cells aerosolized using the FFAG survived better than those aerosolized using the Collison nebulizer. Aerosols generated by the Collison nebulizer and the FFAG preferentially deposited in the lungs and nasal passages of the murine respiratory tract, respectively. However, significant deposition of material also occurred in the gastrointestinal tract after inhalation of both the small (89.7%)- and large (61.5%)-particle aerosols. The aerosols generated by the Collison nebulizer and the FFAG differ with respect to mass distribution, distribution of the entrapped particulates, bacterial survival, and deposition within the murine respiratory tract.     

Quantitative deposition of ultrafine stable particles in the human respiratory tract

Theoretical models of particle deposition in the respiratory tract predict high fractional deposition for particles of less than 0.1 micron, but there are few confirming experimental data for those predictions. We have measured the deposition fraction of a nonhygroscopic aerosol in the human respiratory tract. The aerosol had a count mean diameter of 0.044 micron SD of 1.93, as measured with an electrical aerosol analyzer, and was produced from a 0.01% solution of bis(2-ethylhexyl) sebacate using a condensation generator. Subjects inhaled the aerosol using a controlled respiratory pattern of 1 liter tidal volume, 12/min. Deposition was calculated as the difference in concentration between inhaled and exhaled aerosol of five size fractions corrected for system deposition and dead-space constants. Three deposition studies were done on each of five normal male volunteers. Means (+/- SE) for the five size fractions were 0.024 micron, 0.71 +/- 0.06; 0.043 micron, 0.62 +/- 0.06; 0.075 micron, 0.53 +/- 0.05; 0.13 micron, 0.44 +/- 0.04; and 0.24 micron, 0.37 +/- 0.06. These data demonstrate that deposition of inhaled particles in the 0.024- to 0.24-micron size range is high and increases with decreasing size. These observations agree with and validate predictions of mathematical models.     

Validating CFD predictions of respiratory aerosol deposition: effects of upstream transition and turbulence

A number of computational fluid dynamics (CFD) studies have explored local deposition patterns of inhaled aerosols in the respiratory tract. These studies have highlighted the effects of multiple physiologic, geometric, and particle characteristics on deposition. However, very few studies have reported local or sub-branch quantitative comparisons to in vitro particle deposition data. The objective of this study is to numerically investigate the effects of transition and turbulence on highly localized particle deposition in a respiratory double bifurcation model in order to quantitatively validate CFD results. To perform the validations, local comparisons have been made to a specific in vitro case study of 10 microm particles depositing in a model of respiratory generations G3-G5. To achieve this objective, two geometric cases have been considered. The first case includes only the double bifurcation model. The second case includes a portion of the experimental particle delivery geometry, where transitional flow is expected. To evaluate the effectiveness of two-equation turbulence models in this system, the flow field solutions have been computed using laminar, standard k-omega, and low Reynolds number (LRN) k-omega approximations. Results indicate that even though the Reynolds number remained below the critical limit required for full turbulence, transition and turbulence have a significant impact on the flow field and local particle deposition patterns. For the experimental case considered, turbulence impacted the local deposition of 10 microm particles primarily by influencing the initial velocity and particle profiles. As such, both the laminar and LRN k-omega flow models provided good local quantitative matches to the in vitro deposition data, provided that the correct initial particle profile was specified. Implications of this study include the need for local quantitative validations of particle deposition results, the importance of correct inlet conditions, and the need to consider upstream effects in experimental and computational studies of the respiratory tract. Applications of these results to realistic respiratory geometries will require consideration on upstream flow conditions in the lung, transient flow, and intermittent turbulent structures.     

Particle Deposition in a Child Respiratory Tract Model: In Vivo Regional Deposition of Fine and Ultrafine Aerosols in Baboons

To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region) of radioactive polydisperse aerosols ([d16–d84], equal to [0.15 µm–0.5 µm], [0.25 µm–1 µm], or [1 µm–9 µm]). Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the [1 µm–9 µm] aerosol (72%±17%). The [0.15 µm–0.5 µm] aerosol was associated almost exclusively with thoracic region deposition (84%±4%). Airborne particles in the range of [0.25 µm–1 µm] showed an intermediate deposition pattern, with 49%±8% in the extrathoracic region and 51%±8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the [1 µm–9 µm] aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes.     

CFD simulation of aerosol delivery to a human lung via surface acoustic wave nebulization

Administration of drug in the form of particles through inhalation is generally preferable in the treatment of respiratory disorders. Conventional inhalation therapy devices such as inhalers and nebulizers, nevertheless, suffer from low delivery efficiencies, wherein only a small fraction of the inhaled drug reaches the lower respiratory tract. This is primarily because these devices are not able to produce a sufficiently fine drug mist that has aerodynamic diameters on the order of a few microns. This study employs computational fluid dynamics to investigate the transport and deposition of the drug particles produced by a new aerosolization technique driven by surface acoustic waves (SAWs) into an in silico lung model geometrically reconstructed using computed tomography scanning. The particles generated by the SAW are released in different locations in a spacer chamber attached to a lung model extending from the mouth to the 6th generation of the lung bronchial tree. An Eulerian approach is used to solve the Navier–Stokes equations that govern the airflow within the respiratory tract, and a Lagrangian approach is adopted to track the particles, which are assumed to be spherical and inert. Due to the complexity of the lung geometry, the airflow patterns vary as it penetrates deeper into the lung. High inertia particles tend to deposit at locations where the geometry experiences a significant reduction in cross section. Our findings, nevertheless, show that the injection location can influence the delivery efficiency: Injection points close to the spacer centerline result in deeper penetration into the lung. Additionally, we found that the ratio of drug particles entering the right lung is significantly higher than the left lung, independent of the injection location. This is in good agreement with this fact that the most of airflow enters to the right lobes.     

Nasal-associated lymphoid tissue is a mucosal inductive site for virus-specific humoral and cellular immune responses

Peyer's patches are known as mucosal inductive sites for humoral and cellular immune responses in the gastrointestinal tract. In contrast, functionally equivalent structures in the respiratory tract remain elusive. It has been suggested that nasal-associated lymphoid tissue (NALT) might serve as a mucosal inductive site in the upper respiratory tract. However, typical signs of mucosal inductive sites like development of germinal center reactions after Ag stimulation and isotype switching of naive B cells to IgA production have not been directly demonstrated. Moreover, it is not known whether CTL can be generated in NALT. To address these issues, NALT was structurally and functionally analyzed using a model of intranasal infection of C3H mice with reovirus. FACS and histological analyses revealed development of germinal centers in NALT in parallel with generation and expansion of IgA(+) and IgG2a(+) B cells after intranasal reovirus infection. Reovirus-specific IgA was produced in both the upper respiratory and the gastrointestinal tract, whereas production of reovirus-specific IgG2a was restricted to NALT, submandibular, and mesenteric lymph nodes. Moreover, virus-specific CTL were detected in NALT. Limiting dilution analysis showed a 5- to 6-fold higher precursor CTL frequency in NALT compared with a cervical lymph node. Together these data provide direct evidence that NALT is a mucosal inductive site for humoral and cellular immune responses in the upper respiratory tract.     

Targeting drug delivery to the lungs by inhalation

Most drugs targeted to the respiratory tract are used for their local action. For example, ephidrine for nasal decongestion, beta-2 agonists for bronchodilatation, and inhaled steroids to suppress the inflammation seen in asthmatic airways. Since the drug is delivered directly to its required site, only a small quantity is needed for an adequate therapeutic response, and consequently there is a low incidence of systemic side effects compared with oral or intravenous administration. More recently, it has become apparent that the lining of the respiratory tract, from nasal mucosa to airways and alveoli, may be used for the absorption of a drug for its systemic effect. This route of administration may be particularly attractive if it avoids the metabolic destruction encountered when some drugs are administered by alternative routes (for instance, peptides and proteins are rapidly destroyed by peptidases when Oven by the oral route). If there is a lack ofclinical response to an aerosolized drug, it is important to question whether the drug has failed or whether delivery to the site of action is inadequate. To deliver therapeutic agents by inhalation to the lower respiratory tract, inhaled drug particles must have appropriate aerodynamic characteristics. In addition, the anatomy and pathophysiology of the patient's respiratory tract, mode of inhalation through the inhaler, and the characteristics of the inhalational device itself, may significantly affect drug deposition.     

Management and outcome of winter upper respiratory tract infections in children aged 0-9 years.

Age-specific incidences for upper respiratory tract infections in children from a new-town population during 1975-7 were studied, and 965 consecutive upper respiratory tract infections in children aged under 10 during two winters were analysed in detail. Significantly different management plans made by seven doctors did not correlate with the clinical outcome as judged by complications, recall rates, and demand for treatment for similar episodes in the future. Two hundred and thirty-two children (24%) returned for another consultation for the same episode of upper respiratory tract infection. The main reason for these repeat consultations seemed to be that parental expectations about the natural history of the illness were not fulfilled. More realistic parental expectations might be set and safer clinical standards maintained if doctors warned parents about symptoms such as cough and occasional diarrhoea or vomiting that are commonly associated with upper respiratory tract infections in children.     

Etiologic Diagnosis of Lower Respiratory Tract Infections

Decision as to the role of infection in lower respiratory tract disease requires examination by culture of specimens known to be derived from the infra-laryngeal respiratory tract. Methods that involve the upper respiratory tract in collection of specimens entail the hazard of contamination by microbiota resident in the upper respiratory tract.The extrapulmonary approaches of cutting-needle biopsy and needle aspiration of intrathoracic disease have not been impressively productive of etiologic diagnosis of infections. While open-chest surgical biopsy has been a highly effective means to diagnosis, this approach does have special requirements in facilities and technical skills.Percutaneous transtracheal aspiration of tracheo-broncho-pulmonary secretions-exudates has been productive of useful information. Because of inherent simplicity and safety, transtracheal aspiration should precede resort to more demanding, difficult, dangerous procedures.     

Differential Expression of the Middle East Respiratory Syndrome Coronavirus Receptor in the Upper Respiratory Tracts of Humans and Dromedary Camels

Middle East respiratory syndrome coronavirus (MERS-CoV) is not efficiently transmitted between humans, but it is highly prevalent in dromedary camels. Here we report that the MERS-CoV receptor—dipeptidyl peptidase 4 (DPP4)—is expressed in the upper respiratory tract epithelium of camels but not in that of humans. Lack of DPP4 expression may be the primary cause of limited MERS-CoV replication in the human upper respiratory tract and hence restrict transmission.     

Determining the basic characteristics of aerosols suitable for studies of deposition in the respiratory tract

Studies of aerosol particle deposition in the respiratory tract requires experimental inhalation of artificial model aerosols. The paper formulates some of the most important requirements for the properties of such aerosols. Several suitable fractions were prepared as part of a research project dealing with the use of microporous polymers for diagnostic purposes. 5 fractions of the polymer designated G-gel 60 with the particle size as stated by the manufacturer, ranging from 3 to 7 micron were evaluated using a 16-channel particle dispersity analyzer HIAC/ROYCO MT 3210 with the sensor 1200 and operated by a microprocessor, the equipment being coupled to an APPLE IIe computer. G-gel 60 particles introduced into the aerosol were characterized by the parameters CMAD, MMAD and sg both numerically and graphically. The measurement procedure was found to be very sensitive with respect to all fractions in evaluating the subtile differences between different lot numbers of the aerosol. G-gel 60 fractions characterized both numerically and graphically were compared with the known aerosols from paraffin oil and atmospheric air. The equipment MT 3210 enables prompt determination of the percentages of aerosol particles distribution by size class. The authors conclude that the procedure, both in its numerical and graphical versions, is particularly suitable for the diagnosis of aerosol particles deposition in the respiratory tract, offering a new application for HIAC/ROYCO in the field of medicine. In evaluating atmospheric aerosol in exhaled air, the number of particles was found to be below that in inhaled air, the difference being dependent on the choice of investigation methods. Percentual distribution of deposited particles following one minute ventilation proved to be at its maximum, as regards atmospheric aerosol, in the 0.30-0.50 micron range. The deposition curve was similar to already published curves, being characterized by an S-shaped pattern with maximum deposition in the greater size classes. An analysis of inhaled, exhaled and deposited aerosol suggested that deposited aerosol is more polydisperse and has particles of greater sizes than inhaled aerosol. Investigation of the effect of apnoe on deposition indicated that deposition increased as a function of apnoeic pause.