Optimization of Aerosol Drug Delivery

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Mechanisms of Pharmaceutical Aerosol Deposition in the Respiratory Tract

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Materials and Devices for Bone Disorders. Wear of Orthopaedic Implants and Artificial Joints. 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. Delivery of a therapeutic agent by inhalation has seen increasing applications for many respiratory diseases, including asthma, COPD, allergies, and influenza.

Aerosol delivery has advantages: In addition, the inhalation route has been extensively researched as an alternative for systematic administration of proteins and peptides because of the large surface area in the pulmonary region and rapid absorption of the delivered drug from the alveolar region to the blood. Currently, there are several types of therapeutic aerosol delivery systems, including the pressurized metered-dose inhaler pMDI , the dry powder inhaler DPI , the medical nebulizer, the solution mist inhaler, and nasal sprays.

This knowledge is essential in developing a dosing regimen to deliver the required amount of active compound to the patient. It is also important in determining the range of doses necessary for preclinical toxicology studies and for comparing the efficiency of delivery among different delivery devices. Newman showed through case studies that the clinical effects of an asthma treatment can be correlated directly with the deposited dose in the lung 1. Derom and Pauwels also reached similar conclusions 2. Lung deposition data are very useful to show the bioequivalence between two pMDIs and DPIs or between a new device and an existing device.

Deposition data obtained using human volunteers or physical models of airways are often included in the development of inhalation drugs 3. Standardized techniques of obtaining human deposition data using planar image and single-photon emission tomography for orally inhaled pharmaceutical products are available 4 , 5. Based on these studies, the aerosol transport and deposition mechanisms are well understood. The deposition pattern can be influenced by several factors: The primary aerosol deposition mechanisms may include inertial impaction, sedimentation, diffusion, interception, and electrostatic effects 6 , 8 , 9.

The contribution of these deposition mechanisms is a function of particle size and flow rate in a given region of respiratory tract. Lung deposition models have been used extensively to estimate radiation doses from occupational and ambient exposure to radioactive aerosols as well as inhalation doses of hazardous particulate matter in different environments.

There were also attempts to use these models or others to investigate factors that may affect aerosol drug delivery 3 , 10 — However, prediction of regional deposition of pharmaceutical aerosol using these models has limited success primarily because they underestimate oropharyngeal deposition 3 , 11 , which also leads the overestimation of lung deposition. Current studies of oropharyngeal deposition of several drug delivery systems identify other factors including mouthpiece diameter, particle velocity, and electrostatic effects associated with the delivery system that dominates the transport and deposition of the oropharyngeal region 9 , 13 — Computational fluid dynamic CFD simulation of the aerosol transport and deposition in the respiratory tract has provided important insight into these processes.

The human respiratory tract is a complex system. Aerosol deposition in the lung has been studied in vivo using human volunteers 17 — 19 ; in vitro using physical airway replicas 20 — 22 ; and theoretically using mathematical models In these studies, the respiratory tract is usually divided into three major regions including the extrathoracic, thoracic, and pulmonary regions. The human respiratory tract can be divided into three anatomical regions as shown in Fig.

The extrathoracic or head airway including the naso-oro-pharyngo-laryngeal region is the entry to the respiratory tract and the first defense against hazardous inhaled material. The tracheobronchial TB tree or conducting airway includes the trachea and 16 generations of branching airways. Gas exchange takes place in the pulmonary region P , which consists of alveolar ducts and alveolar sacs. Some people are habitual oral breathers even at rest. When an airborne particle is transported near a person, it may be inhaled and enters the respiratory tract through either nasal or oral passages.

The ability of the particle to enter the head airway, also known as its inhalability, is a function of its aerodynamic diameter. Inhalability is a fraction of airborne particles entering the human airway. Most of the experimental data on inhalability has been obtained in aerosol wind tunnels.

Once the particle enters the respiratory tract via either the nose or mouth, it may be deposited in different regions of the respiratory tract. In fact, deposition by impaction in the oropharyngeal region remains a major portion of the emitted dose for pMDI and DPI devices. In the small airways and alveolar region, deposition by sedimentation is the major deposition mechanism of inhaled particles.

Interception deposition is important for elongated particles such as fibrous aerosols when the long particle dimension is comparable with the pulmonary airway dimension. Pharmaceutical aerosol may carry electrostatic charges during the generation and transport of the aerosol, especially for DPI and pMDI devices Although the aerosol charge status may vary with many factors including the material, expedients, formulation, and material used in the devices, the amount of electrostatic charges on aerosol from several devices was deemed to affect the deposition. Electrostatic effects including image and space charge forces are found to enhance particle deposition if the number of charges on particles exceeds a threshold 9 , 27 — Condensation of water in the humid environment of the respiratory tract may cause particles to grow and change the way that they move through the respiratory tract.

The efficiency of particle deposition and the spatial distribution of deposition in the human respiratory tract have been measured experimentally in human volunteers and physical models of airway replicas using spherical test particles tagged with radiolabels or fluorescent materials. These models have been used extensively to estimate the radiation dose as a result of exposure to radioactive aerosols as well as inhalation dosimetry of hazardous particulate matter in the ambient and occupational environments.

Theoretical models utilize simplified airway geometries and aerosol deposition mechanisms including impaction, sedimentation, diffusion, and interception to derive deposition equations in each of the airway regions. Total and regional aerosol depositions are then calculated with input information of particles with known characteristics size, density, and shape and physiological conditions tidal volume and breathing rate. Experimental data obtained in vivo and in vitro were used to verify the deposition equations or regional and total deposition in the respiratory tract. The deposition fractions are a function of aerodynamic diameter in men with nasal breathing for a tidal volume of 1.

The plot shows that, for particles larger than 0. On the other hand, nasal and laryngeal deposition also increases when particle size decreases from 0. Particles in the size range between 0. Deposition fractions are a function of aerodynamic diameter in man with mouth breathing for a tidal volume of 1.

One major difference in mouth breathing as opposed to nasal breathing is that deposition in the oral airway is much less than the deposition in the nasal airway for particles of all sizes between 0. As a result, there is substantial deposition in the TB and P regions when mouth breathing is the primary inhalation method. Therefore, pharmaceutical devices for pulmonary delivery such as pMDIs, DPIs, and nebulizers are generally delivered via oral inhalation to reduce deposition in the head airway and maximize dose to the lower airways.

On the other hand, nasal sprays are designed to deposit in the nasal passages for local treatments. Human deposition data has been used as the technical basis to formulate the size selection criteria of sampling methods for designing particulate samplers such as PM10, inhalable, and respirable samplers The information is also used for the design of aerosol drug delivery systems. The inhalation delivery route of pharmaceutical drugs including nasal and oral delivery depends on the target regions of the drugs.

Nasal sprays and other devices are used to deliver drugs into the nasal cavity using the nasal inhalation route for local decongestion, influenza vaccines, or to ameliorate allergic conditions. Other aerosol drugs targeting tracheobronchial and pulmonary airways to treat respiratory diseases such as asthma, cystic fibrosis, COPD, tuberculosis, and allergies are delivered by the oral inhalation route because particle deposition or losses in the extrathoracic region are much lower for oral inhalation compared to nasal inhalation as shown in Fig.

More recently, inhalation delivery has been extensively researched as an alternative for systematic administration of proteins and peptides. This inhalation delivery has been done primarily by oral inhalation for delivery to the pulmonary region. In addition, this inhalation delivery has also been carried out by nasal inhalation to the nasal cavity to be absorbed and transferred to the circulation. Estimates of lung deposition patterns from the deposition models have been used as a general guide in the design of aerosol drug delivery.

The FPF is usually estimated by measuring particle size in vitro using inertial instruments Depending on the instrument, the FPF is calculated differently.

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The FPF has been used to correlate the in vivo deposition obtained by gamma scintigraphy. Clark showed that changes in FPF produced by different spacer devices are mirrored by changes in lung deposition He concluded that FPF data alone are unreliable as a predictor of the relative deposition from two devices with markedly different spray characteristics e. Correlation of lung deposition with the fine particle fraction Attempts have been made to estimate lung deposition efficiency directly from in vitro measurement of particle size distribution and breathing rates.

Because aerosol drug delivery is different from the natural breathing of particulate matter, modifications of existing lung deposition model are needed. The third modification is the estimated oropharyngeal deposition for oral delivery. Following the suggestion made by Pritchard et al. The total was then the calculated deposition fraction in the oropharyngeal region. Based on these modifications, the Lung Dose Evaluation Program LUDEP software was used to estimate the deposition pattern of pulmonary delivery of pharmaceutical aerosol via mouth breathing and compared in vivo deposition pattern obtained with gamma scintigraphy 3 , 6 , Data from a gamma scintigraphic study of three Pari nebulizers 36 were used for comparison of values calculated by LUDEP.

The droplet size distribution was measured using the Malvern laser diffraction technique Malvern Instruments. The mass median diameters MMDs were between 4 and 5.

The GSD of 2. Ten healthy adult volunteers took part in the study. Breathing information was not reported. The MMD was 4. The deposition pattern showed that The oropharyngeal deposition was The regional deposition patterns and fraction of expired air of the calculated values were within the range of the experimental error, indicating good agreement.

Similar results were obtained for several other nebulizers having similar particle sizes, indicating good agreement between the predicted deposition patterns and agreed with in vivo data 3 , Additional in vivo data were also used for comparison, for deposition in the lung and oropharyngeal region 39 — In general, the LUDEP method underestimated the oropharyngeal deposition and overestimated the lung deposition and drug expiration. DPIs including Spinhaler, Rotahaler, Diskhaler, and Turbuhaler use inspiratory flow to aerosolize the powder and the rotor, screen, or flow path to create turbulence in order to break up aggregates and reduce the particle size.

An example is the deposition pattern of the budesonide inhaled via the Turbulhaler in healthy subjects The predicted deposition shows lower oropharyngeal and higher lung deposition than the experimental data. Additional in vivo deposition data using DPIs were also used for comparison 3 , 12 , 39 , 47 — In summary, the application of existing lung models developed for inhalation of particulate matter in the ambient or occupational environments for dose estimates of pharmaceutical aerosols for pulmonary delivery via mouth breathing has mixed results.

While the model adequately predicted deposition dose in aerosol delivery using nebulizers, prediction for aerosol delivery using both DPIs and pMDIs was not satisfactory. The high deposition in the oropharyngeal region reduces the amount of drugs getting to the targeted tissue in the lower airway. This may cause side effects and defeat the purpose of oral route of inhalation for pulmonary delivery. Recent understandings of the aerosol transport and deposition processes in the oropharyngeal regions have made substantial progress through studies in realistic upper airway replicas and CFD simulation.

Studies with airway replicas made from cadaver or MRI scans provided reproducible deposition data which can be used to study the deposition mechanism. Realistic airway geometry has also been used in the CFD simulation to study the air flow and deposition processes. Detailed airway dimensions in 0. This Lovelace Respiratory Research Institute LRRI replica was used in the in vitro studies of nanoparticle deposition and coarse particle deposition of micro-metered sizes using standard test aerosols at constant inspiratory flow rates 20 , The deposition data showed a monotonic increase with the impaction parameter, indicating that impaction is the dominant deposition mechanism in the oropharyngeal airway.

The deposition efficiency is also in the same range of data obtained in the in vivo deposition results as shown in Fig. This oral airway geometry has been used in the CFD simulation to study the flow and aerosol transport 51 — The primary characteristics of the axial flow fields are skewed velocity profiles with the maximum velocity shifted to the outer bend generated by the centrifugal force in the curved portion from the oral cavity to the pharynx.

There are also secondary flows in the oral cavity. Deposition efficiency obtained from the CFD simulation agreed well with the experimental data. These studies show that inertial impaction by the curved streamline of the main flow in the oropharyngeal region at the rear of the oral cavity and deposition caused by a constriction in the larynx is the dominant deposition mechanism.

Oral deposition efficiency in a human airway replica as a function of the impaction parameter and flow rate The solid curve is the best-fitted curve. Comparison of oral deposition in the replica with reported in vivo deposition data. The right panel shows the axial velocity contours magnitudes in centimeters per second and secondary velocity vectors at different cross sections with permission from Kleinstreuer and Zhang This model is an average geometrical mouth—throat based on data from a CT scan, MRI scan, and living subjects.

This idealized model has been the basis of many deposition studies, including deposition in aerosol drug delivery devices 14 , 56 , A recent study showed that aerosol deposition in the idealized replica is in close agreement with those in the LRRI realistic mouth—throat replica for liquid aerosol and solid aerosol when the idealized replica is coated to prevent particle bounce The same study also showed that the deposition in USP induction port was much lower.

They suggested that one reason for the high oropharyngeal deposition may be caused by the mouthpiece design of DPIs. Oropharyngeal deposition in an idealized mouth and throat model was measured. However, deposition for the two DPIs was significantly higher than the straight tube, up to 14 times higher. In a follow-up study, DeHaan and Finlay measured deposition in an idealized oral cavity replica The results were shown for a given particle size and flow rate: Deposition efficiency does not correlate with the impaction diameter, d ae 2 Q, which does not include the inlet diameter.

They also performed deposition in the same oral replica for six commercial DPIs, and the deposition results follow the same empirical equation. These studies prove that deposition by the impinging turbulent jet from the narrow diameter of the DPI mouthpiece is the main mechanism for the enhanced deposition in the oropharyngeal region.

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In addition, the oropharyngeal deposition does not increase with the inspiratory flow rate, indicating that the impaction model based on the bulk inspiratory flow in the oral cavity cannot explain the deposition mechanism. In a pMDI device, when the canister valve is actuated, a metered volume of highly pressurized fluid containing the drug and propellant is released through a small nozzle typically 0. The instability of the high-speed jets breaks up into small droplets which also undergo evaporation.

The mean volume droplet size was from 5. There were two phases in the formation of droplets.

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