Dry powder aerosol delivery systems: current and future research directions.

Development of dry powder aerosol delivery system involves powder production, formulation, dispersion, delivery, and deposition of the powder aerosol in the airways. Insufficiency of conventional powder production by crystallization and milling has led to development of alternative techniques. Over the last decade, performance of powder formulations has been improved significantly through the use of engineered drug particles and excipient systems which are (i) of low aerodynamic diameters (being porous or of low particle density), and/or (ii) less cohesive and adhesive (via corrugated surfaces, low bulk density, reduced surface energy and particle interaction, hydrophobic additives, and fine carrier particles). Early insights into particle forces and surface energy that help explain the improvement have been provided by analytical techniques such as the atomic force microscopy (AFM) and inverse gas chromatography (IGC). Relative humidity is critical to the performance of dry powder inhaler (DPI) products via capillary force and electrostatic interaction. Electrostatic charge of different particle size fractions of an aerosol can now be measured using a modified electrical low-pressure impactor (ELPI). Compared with powders, much less work has been done on the inhaler devices at the fundamental level. Most recently, computational fluid dynamics has been applied to understand how the inhaler design (such as mouthpiece, grid structure, air inlet) affects powder dispersion. The USP throat is known to under-represent the oropharyngeal deposition of DPI aerosols. Studies using magnetic resonance imaging (MRI) model casts have been undertaken to explain the inter- and intra- subject variation in oropharyngeal deposition. Most of the lung deposition studies performed on commercial products did not allow a thorough understanding of the determinants affecting in vivo lung deposition. A more systematic approach would be necessary to build a useful database on the dependence of lung deposition on the breathing parameters, inhaler design, and powder formulation properties.     

The role of dispersion in particle deposition in human airways.

Aerosol dispersion and deposition are processes that occur concurrently in human airways. However, dispersion has not been properly accounted for in most deposition models. In this paper we have incorporated the latest understanding of dispersion into a dosimetry model and study the influence of dispersion on particle deposition in the lung. We show that dispersion influences the total deposition of inhaled particles and in particular increases the pulmonary deposition of fine mode particles. We also discuss how dispersion can help elucidate a number of clinical and epidemiologic results associated with particle deposition in the lung.     

Effect of separation characteristics between salbutamol sulfate (SS) particles and model carrier excipients on dry powder for inhalation]

Most often dry powder for inhalation are formulated as ordered mixtures of a carrier excipient and a micronized drug substance. In the present study, model powder blends were prepared from a mixture of lactose alpha-monohydrate, micro-crystalline cellulose pellets or synthesized sugar as carrier particles, and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO dry powder inhaler (DPI) and their in vitro deposition properties were evaluated by a twin impinger (TI). The separation force between SS particles and carrier particles was investigated by the centrifuge method. In addition, the use of the air jet sieve (AJS) method was investigated to assess the separation behavior of drug particles from carrier excipient. Powder blends were sieved through a 325 mesh wire screen of an air jet sieve at an air pressure of 1500 Pa. The amount of drug deposited at the carrier surface was analysed before and after the sieving to calculate the percentage of the drug retained. A relationship was found between in vitro deposition properties (fine particle fraction, FPF) and the separation characteristics obtained by the centrifuge method and by the AJS method. The AJS method might be a suitable alternative for evaluating separation of a drug particle from carrier particles and hence can be used for the formulation screening of the dry powder inhalation.     

干粉吸入剂空气动力学分散模型的建立和验证

在Weiler干粉粒子聚集体全分散理论模型基础上,以硫酸沙丁胺醇为模型药物,建立了一种更加深入的千粉吸入剂空气动力学分散模型.硫酸沙丁胺醇干粉吸入剂体外沉积试验表明,该模型可预测干粉粒子的空气动力学分散行为,并可结合计算流体动力学,估算干粉吸入剂在吸入装置中的分散及微细粒子分数.     

Deposition Patterns of Aerosolized Drugs Within Human Lungs: Effects of Ventilatory Parameters

A mathematical model for inhaled aerosolized drugs is validated by comparisons of predicted particle deposition values with experimental data from adult subject inhalation exposure tests. The model is subsequently used to study the effects of ventilatory parameters on particle deposition patterns within the human lung. By altering breathing profiles, deposition values can be affected regarding quantity delivered and spatial location. Increased tidal volumes and breath-holding times increase deposition in the pulmonary region, while increased inspiratory flow rates increase deposition in the tracheobronchial region. Based upon fluid dynamics considerations (Reynolds numbers), an original method of partitioning the lung is also presented. The model has implications with regard to aerosol therapy, indicating that the efficacies of inhaled pharmacological drugs in the prophylaxis and treatment of airway diseases can be improved by regulating breathing profiles to deposit particles selectively at prescribed sites within the lung.     

Mutual enhancements of CFD modeling and experimental data: a case study of 1-mum particle deposition in a branching airway model

In order to better understand aerosol dynamics and deposition in the complex flow field of the respiratory tract, both in vitro experiments and numerical modeling techniques have widely been employed. Computational fluid dynamics (CFD) modeling offers the flexibility of easily modifying system parameters such as flow rates, particle sizes, system geometry, and heterogeneous outlet conditions. However, a number of numerical errors and artifacts can lead to nonphysical CFD results. Experimental methods offer the advantage of physical realism; however, parameter variation is often difficult. The objective of this study is to illustrate the use of CFD to enhance the understanding of experimental results. In parallel, the selected experimental results have been used to partially validate the CFD predictions. A specific case study has been considered focusing on 1-mum particle depositions in a physiologically realistic bifurcation (PRB) model of respiratory generations 3-5. Previous experiments in this system report a deposition rate of approximately 0.01%. An in-depth CFD analysis has been employed to evaluate two cases of the empirical model. The first case consists of only the PRB double bifurcation geometry. The second case includes a portion of the experimental particle delivery system, which may influence the entering velocity and particle profiles. To assess the influence of upstream transition and turbulence, each of the two cases considered has been evaluated using laminar and low Reynolds number k-omega approximations. Results indicate that both upstream flow effects and turbulent or transitional flow play a significant role in determining the deposition of 1-mum particles in the model considered. Simulating upstream flow effects and laminar flow was required to match the empirically reported deposition fraction and provided a two orders of magnitude improvement over initial CFD estimates. This study highlights the need to consider the effects of experimental particle generation systems on velocity and particle profiles entering respiratory models. Future work is necessary to investigate the mechanisms responsible for the experimentally observed local deposition patterns.     

Mutual Enhancements of CFD Modeling and Experimental Data: A Case Study of 1-μm Particle Deposition in a Branching Airway Model

In order to better understand aerosol dynamics and deposition in the complex flow field of the respiratory tract, both in vitro experiments and numerical modeling techniques have widely been employed. Computational fluid dynamics (CFD) modeling offers the flexibility of easily modifying system parameters such as flow rates, particle sizes, system geometry, and heterogeneous outlet conditions. However, a number of numerical errors and artifacts can lead to nonphysical CFD results. Experimental methods offer the advantage of physical realism; however, parameter variation is often difficult. The objective of this study is to illustrate the use of CFD to enhance the understanding of experimental results. In parallel, the selected experimental results have been used to partially validate the CFD predictions. A specific case study has been considered focusing on 1-μm particle depositions in a physiologically realistic bifurcation (PRB) model of respiratory generations 3–5. Previous experiments in this system report a deposition rate of approximately 0.01%. An in-depth CFD analysis has been employed to evaluate two cases of the empirical model. The first case consists of only the PRB double bifurcation geometry. The second case includes a portion of the experimental particle delivery system, which may influence the entering velocity and particle profiles. To assess the influence of upstream transition and turbulence, each of the two cases considered has been evaluated using laminar and low Reynolds number k–ω approximations. Results indicate that both upstream flow effects and turbulent or transitional flow play a significant role in determining the deposition of 1-μm particles in the model considered. Simulating upstream flow effects and laminar flow was required to match the empirically reported deposition fraction and provided a two orders of magnitude improvement over initial CFD estimates. This study highlights the need to consider the effects of experimental particle generation systems on velocity and particle profiles entering respiratory models. Future work is necessary to investigate the mechanisms responsible for the experimentally observed local deposition patterns.     

Parametric simulation of drug release from hydrogel-based matrices

Objectives In this work a model recently proposed to describe the drug release from hydrogel‐based matrices was applied to describe the fractional drug release from matrices based on hydroxypropylmethylcellulose (HPMC) and diclofenac. Methods The model, firstly proposed to describe the behaviour of systems based on HPMC and theophylline and a single set of preparation variables, is based on mass balances and transport phenomena evaluation and it was solved by an FEM‐based numerical code. The experimental data on the HPMC–diclofenac matrices, taken from literature, have been obtained by varying the drug loading ratio, the compression force, the powder size of both the drug and the polymer. Key findings A good agreement between experimental data and model predictions, as calculated in the present work, was obtained without the use of any adjustable parameters. Conclusions The predictive nature of the model has been confirmed, even changing the drug molecule and other preparative parameters.     

In Vitro and In Vivo Lung Deposition of Coated Magnetic Aerosol Particles

The magnetic induced deposition of polydispersed aerosols composed of agglomerated superparamagnetic particles was measured with an in vitro model system and in the mouse trachea and deep lung for the purpose of investigating the potential of site specific respiratory drug delivery. Oleic acid coated superparamagnetic particles were prepared and characterized by TEM, induced magnetic moment, and iron content. The particles were dispersed in cyclohexane, aerosolized with an ultrasonic atomizer and dried by sequential reflux and charcoal columns. The fraction of iron deposited on glass tubes increased with particle size and decreasing flow rate. High deposition occurred with a small diameter tube, but the deposition fraction was largely independent of tube size at larger diameters. Results from computational fluid dynamics qualitatively agreed with the experimental results. Enhanced deposition was observed in the mouse lung but not in the trachea consistent with the analysis of the aerodynamic time allowed for deposition and required magnetic deposition time.     

Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution

Aqueous colloidal dispersions of amorphous cyclosporin A (CsA) nanoparticles, intended for pulmonary delivery, were formed by antisolvent precipitation and stabilized with 10% polysorbate 80. Dissolution of the dispersion of CsA nanoparticles produced supersaturation values 18 times the aqueous equilibrium solubility. Nebulization of the dispersion to mice produced therapeutic lung levels and systemic concentrations below toxic limits. The sizes of the aerosolized aqueous droplets are optimal for deep lung deposition, whereas the amorphous drug nanoparticles facilitate rapid dissolution. A dissolution/permeation model was developed to characterize the effects of particle size, solubility, and drug dose on the absorption half-lives of poorly water soluble drugs in the alveolar epithelium. For crystalline 3 microm particles with a solubility of 1 microg/mL, the half-life for absorption was estimated to be 500 min. The half-life may be reduced to less than 1 min by increasing the solubility by a factor of 100 with an amorphous form as well as by decreasing the particle size 10-fold. The in vitro and in vivo data, as well as the dissolution/permeation model, indicate that nebulization of amorphous nanoparticle suspensions has the potential to enhance lung epithelial absorption markedly for poorly water soluble drugs, relative to respiratory delivery of crystalline, micron-sized particles.     

Effect of mixing of fine carrier particles on dry powder inhalation property of salbutamol sulfate (SS)

The most commonly used formulations for dry powder inhalations are binary ordered mixes composed of micronized drugs and coarse carriers. An optimal dry powder aerosol formulation should possess an optimal inhalation property and a good flow property. These characteristics are especially important for a multidose dry powder inheler (DPI). In the present study, model powder blend were prepared consisting of synthesized sugar (different particle sized isomalt; IM-PF, IM-FS, IM-F) as a carrier and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO DPI (SkyePharma AG) and in vitro deposition properties (fine particle fraction, FPF) were evaluated by a twin impinger (TI) at a flow rate of 60 l/min. The separation property between SS and carrier particles was investigated by the centrifuge method and air jet sieve (AJS) method. It was found that FPF decreased with increasing carrier particle size. However, a large carrier particle possesses a good flow property. Therefore, the effect of mixing of fine carrier particles (IM-PF) into the large carrier particles (IM-FS) on dry powder inhalation property was investigated. When the proportion of IM-PF (fine carrier) increase from 0% to 25% of the total carrier powder blend, the FPF also increases from 16.7% to 38.9%. It is concluded that the effect of mixing of fine carrier particles might be a suitable method for improving the dry powder inhalation properties.     

Dose delivery late in the breath can increase dry powder aerosol penetration into the lungs.

In addition to aerosol particle size and mode of inhalation, the time-point of dose delivery during inhalation may be an important factor governing the intrapulmonary distribution of aerosolized drug. To generate different intrapulmonary deposition patterns of a drug model aerosol, a device with the capability of delivering small amounts of technetium-99m-labeled lactose dry powder at pre-set time-points during inhalation was developed. A single dose of the radioaerosol was delivered after inhalation of 20% (A) or 70% (B) of the vital capacity inhaled through the device. Twelve healthy subjects were studied in a randomized crossover fashion. Planar gamma scintigraphy was carried out, and the penetration index, PI, defined as the ratio of peripheral to central lung zone deposition of radioactivity, was estimated. A significant increase in PI from 3.0 (A) to 3.7 (B) was observed with the change from early to late delivery of the dose (p < 0.01). No difference in the total amount of radioactivity within the lungs could be detected. In conclusion, independent of total pulmonary deposition, deeper dry powder aerosol penetration into the lungs was found for the dose delivered at near end instead of at the beginning of inhalation. By computational modeling of the aerosol transport and deposition, that finding was mechanistically explained by differences in airway caliber as a consequence of the level of lung inflation at the time-point of dose delivery.     

Particle deposition in human respiratory system: Deposition of concentrated hygroscopic aerosols

In the nearly saturated human respiratory tract, the presence of water-soluble substances in the inhaled aerosols can cause change in the size distribution of the particles. This consequently alters the lung deposition profiles of the inhaled airborne particles. Similarly, the presence of high concentration of hygroscopic aerosols also affects the water vapor and temperature profiles in the respiratory tract. A model is presented to analyze these effects in human respiratory system. The model solves simultaneously the heat and mass transfer equations to determine the size evolution of respirable particles and gas-phase properties within human respiratory tract. First, the model predictions for nonhygroscopic aerosols are compared with experimental results. The model results are compared with experimental results of sodium chloride particles. The model reproduces the major features of the experimental data. The water vapor profile is significantly modified only when a high concentration of particles is present. The model is used to study the effect of equilibrium assumptions on particle deposition. Simulations show that an infinite dilution solution assumption to calculate the saturation equilibrium over droplet could induce errors in estimating particle growth. This error is significant in the case of particles of size greater than 1 μm and at number concentrations higher than 10⁵/cm³.     

The Prediction of Variability Occurring in Fluidized Bed Coating Equipment. II. The Role of Nonuniform Particle Coverage as Particles Pass Through the Spray Zonemr

The purpose of this work was to evaluate the relative importance of particle circulation and particle-to-particle mass coating distribution on the overall mass coating distribution obtained in a Wurster process. A series of batch coating experiments was carried out over a range of operating conditions, in order to evaluate the particle-to-particle variation in the mass distribution of coating material deposited during batch coating operations. Results showed that the major component of variance was due to the variation in the amount of coating received per particle per pass through the spray zone. The variation in the number of times a particle passed through the spray zone was considerably less important. Two models were developed to explain the results of the experimental program. The first model categorized particles moving through the spray zone as either receiving coating or not. Thus, the distribution of coating material per particle per pass is described by a Bernoulli probability distribution. Using this picture of the spray process, the number of particles receiving coating during any given pass through the spray zone was found to vary between 2 and 6%. A second model was developed to explain the major cause of variation. This model explains the variation in terms of the hindering or sheltering effect that particles close to the source of the spray have on particles farther away. Although the agreement of model predictions with experimental results is only fair, it is believed that this model captures the main cause of particle-to-particle variation occurring in batch coating operations and thus is the first model to explain this phenomenon.     

The prediction of variability occurring in fluidized bed coating equipment. II. The role of nonuniform particle coverage as particles pass through the spray zone

The purpose of this work was to evaluate the relative importance of particle circulation and particle-to-particle mass coating distribution on the overall mass coating distribution obtained in a Wurster process. A series of batch coating experiments was carried out over a range of operating conditions, in order to evaluate the particle-to-particle variation in the mass distribution of coating material deposited during batch coating operations. Results showed that the major component of variance was due to the variation in the amount of coating received per particle per pass through the spray zone. The variation in the number of times a particle passed through the spray zone was considerably less important. Two models were developed to explain the results of the experimental program. The first model categorized particles moving through the spray zone as either receiving coating or not. Thus, the distribution of coating material per particle per pass is described by a Bernoulli probability distribution. Using this picture of the spray process, the number of particles receiving coating during any given pass through the spray zone was found to vary between 2 and 6%. A second model was developed to explain the major cause of variation. This model explains the variation in terms of the hindering or sheltering effect that particles close to the source of the spray have on particles farther away. Although the agreement of model predictions with experimental results is only fair, it is believed that this model captures the main cause of particle-to-particle variation occurring in batch coating operations and thus is the first model to explain this phenomenon.     

Aerosol deposition modeling using ACSL

An aerosol deposition model has been written for inclusion into physiologically based pharmacokinetic (PBPK) models, allowing PBPK model based risk assessments to be performed for aerosolized materials. Previously, PBPK models could only treat inhaled gases and vapors. The deposition model employs a semi-empirical equation to describe extrathoracic deposition and employs data concerning the geometry of the thoracic conducting airways as well as that of the gas exchange regions of the lung to compute the deposited aerosol mass based on aerosol diffusion, sedimentation, and impaction. Provisions are made to allow calculations for polydisperse aerosols whose size distribution and mass vary with time. Variations in the model subject's respiration can be accommodated through selection of respiratory parameters at model startup as well as through consideration of carbon dioxide stimulation of respiration. The model is compared with other similar calculations and experimental data to validate the calculations. An example model application is presented in the form of a comparison of two inhalation atmospheres, one from an inhalation toxicity study and one from a similar atmosphere produced for fire extinguishing agent testing.     

Dry powder inhalation of hemin to induce heme oxygenase expression in the lung.

The purpose of this study was to formulate hemin as a powder for inhalation and to show proof of concept of heme oxygenase 1 (HO-1) expression in the lungs of mice by inhalation of hemin. Hemin was spray dried from a neutralized sodium hydroxide solution. The particle size distribution of the powder was between 1 and 5 microm. Dispersion from the Twincer dry powder inhaler showed a fine particle fraction (<5 microm) of 36%. A specially designed aerosol box based on the Twincer-inhaler was used for a proof of concept study of HO-1 induction by inhalation of hemin in mice. The aerosol in the exposure chamber of the aerosol box remained aerosolized up to 5 min. A rhodamin B containing aerosol was used to show that the aerosol box gave deposition over the entire lung indicating the suitability of the model. Additionally, inhalation of hemin showed a dose dependent increase in HO-1 protein expression in the lungs. In conclusion, hemin was successfully formulated as a powder for inhalation and the inhalation model allowed controlled HO-1 expression in the lungs of mice. Future studies investigating the utility of inhaled hemin in treating disease states are warranted.