Deposition Of Drug Particles Research Articles

Coupled Discrete Phase and Eulerian Wall Film Models for Drug Deposition Efficacy Analysis in Human Respiratory Airways.

The current study explores the effectiveness of drug particle deposition into human respiratory airways to cure various pulmonary-bound ailments. It has been assumed that drug solutions are inhaled in the form of tiny droplets or mist, which after striking create a thin layer along the inner surface of airways where the virus initially resides to infect the human body. A coupled Eulerian wall film (EWF) and discrete phase model (DPM) based simulation approach is used to capture these dynamics. Here, the Lagrangian DPM technique tracks the dynamics of tiny droplets, while the liquid layer formation after striking is captured using the Eulerian thin film approximations or the EWF model. Previous studies in this field primarily employed only the DPM method, which is inadequate to predict the poststriking dynamics of drug layer deposition and their spread to neutralize the respiratory virus. The drug delivery effectiveness is characterized by three different particle sizes, 1, 5, and 10 μm at the inhalation rates of 15, 30, and 60 L per minute (LPM). It has been found that the size of the drug particles significantly influences drug delivery effectiveness. The film thickness increases monotonically with particle sizes and inhalation rates. However, this increase in averaged film thickness is prominent in the range 5 to 10 μm (≈60%) compared to 1 to 5 μm (≈10%) droplet sizes at generation level 4 (G4). The other deposition parameters, e.g., deposition fraction, deposition density, and area coverage) roughly show similar behavior with the increase in droplet sizes. Therefore, it is recommended to vary the droplet sizes between 5 and 10 μm for better deposition effectiveness. The sizes of more than 10 μm mostly stuck into the oral cavity and cannot reach the targeted generations. In contrast, less than 5 μm may reach much deeper generations than the targeted one.

Effect of Nasal Inhalation on Drug Particle Deposition and Size Distribution in the Upper Airway: With Soft Mist Inhalers.

Delivery of drugs to the lungs is commonly achieved using nasal and/or oral breathing-assisted techniques. The route of inhalation can substantially change the fate of inhaled droplets. The Respimat® Soft Mist™ Inhaler (SMI) is a commercially available efficient inhaler with 40-60% effectiveness. In the present study, we used computational fluid dynamics (CFD) with a custom setup to investigate the effect of a combined oral/nasal inhalation route on the SMI's regional droplet deposition, size distribution, and flow field. Our setup used a modified induction port (MIP) to mimic nasal inhalation inside the human respiratory tract. Six different oral/nasal flow rate ratios inside the MIP were applied (total flow rate of 30l/min). An overall good agreement was achieved between simulation outcomes and in vitro results. Our results confirmed that the combined inhalation route affects the flow field, altering the MIP's droplet deposition and size distribution. The lowest depositional loss, mainly in the mouth area, was observed at oral/nasal flow rate ratios of O/N = 1 and O/N = 2 with 3% and 7.7% values, respectively. Droplets with a 2-5µm diameter range showed the highest droplet mass inside the MIP at all combined flow rates. We observed less intense vortexes followed by a lower level of turbulent kinetic energy at the oral/nasal ratio of 1. Increasing the relative humidity (RH) at oral/nasal flow rate ratios of 0.07, 1, and 14 led to an increase in droplet deposition at the outlet of the MIP.

Olfactory drug delivery with intranasal sprays after nasal midvault reconstruction

Conductive olfaction and nose to brain drug delivery are important processes that remain limited by inadequate odorant or drug delivery to the olfactory airspace. Primary challenges include anatomic barriers and poor targeting to the olfactory region. This study uses computational fluid dynamics to investigate the effects of nasal midvault surgery on olfactory drug delivery with intranasal sprays. Soft tissue elevation, spreader flaps, and spreader grafts were performed on two fresh cadaveric specimens, using computed tomography for airway reconstruction. Nasal airflow and drug particle transport simulations were performed under these conditions: inhalation rate (15, 30 L/min), spray velocity (1, 5, 10 m/s), spray location (top, bottom, center, medial, lateral), head position (upright, supine, forward, backward), and particle size (1–100 µm). Simulation results were used to calculate drug particle deposition to the olfactory airspaces and bulbs. Total olfactory deposition was < 5% but attained a maximum of 36.33% when sorted by particle size. There was no association between nasal midvault surgery and olfactory deposition. No single parameter or technique demonstrated superior olfactory deposition, but smaller particle size, slower spray velocity, and higher inhalation rate tended to optimize olfactory deposition, providing important implications for future intranasal spray and drug design to target the olfactory airspace.

Non-spherical drug particle deposition in human airway using computational fluid dynamics and discrete element method

Currently, the air pollution and the respiratory disease problems that affect human health are increasing rapidly. Hence, there is attention for trend prediction of the located deposition of inhaled particles. In this study, Weibel’s based human airway model (G0-G5) was employed. The computational fluid dynamics and discrete element method (CFD-DEM) simulation was successfully validated by comparison to the previous research studies. The CFD-DEM achieves a better balance between numerical accuracy and computational requirement when comparing with the other methods. Then, the model was used to analyze the non-spherical drug transport with different drug particle sizes, shapes, density, and concentrations. The results found that all the studied factors affected the drug deposition and particle out-mass percentage except the drug concentration. The drug deposition was increased with the increasing of particle size and particle density due to the influence of particle inertia. The Tomahawk-shaped drug deposited easier than the cylindrical drug shape because of the different drag behavior. For the effect of airway geometries, G0 was the maximum deposited zone and G3 was the minimum deposited zone. The boundary layer was found around bifurcation due to the shear force at the wall. Finally, the knowledge can give an essential recommendation for curing patients with pharmaceutical aerosol. The design suggestion of a proper drug delivery device can be summarized.

Numerical simulation investigation of drug deposition process during nasal administration with auxiliary airflow

Successful delivery of drugs to the Olfactory region (OR) is the key to treating diseases through the nasal cavity. The purpose of this paper is to investigate the effect of auxiliary airflow on particle deposition in the OR during nasal drug administration. A realistic 3D nasal ensemble model was reconstructed from CT scans of the head of a healthy adult. Computational fluid dynamics (CFD) was used to simulate the effect of auxiliary airflow on the deposition of drug particles in the OR during nasal administration. The discrete phase model (DPM) was adopted to track the deposition trajectories of drug particles. Three auxiliary airflows were selected together with three spray cone angles, four particle sizes, five drug particle delivery velocities and three specific injection positions on the deposition fraction of drug particles in the OR were analyzed. The results indicated that the effect of auxiliary airflow on the deposition fraction of drug particles of different particle sizes in the OR is significant. The delivery efficiency of injection position C is always the greatest. A delivery velocity of 15 m/s is more favorable for nasal administration and the effect of spray cone angle is proportional to the auxiliary airflow. Computational results should be helpful for experimental studies and future nasal optimization.

Transport and deposition of beclomethasone dipropionate drug aerosols with varying ethanol concentration in severe asthmatic subjects

This study aims to assess the effects of varying an ethanol co-solvent on the deposition of drug particles in severe asthmatic subjects with distinct airway structures and lung functions using computational fluid dynamics. The subjects were selected from two quantitative computed tomography imaging-based severe asthmatic clusters, differentiated by airway constriction in the left lower lobe. Drug aerosols were assumed to be generated from a pressurized metered-dose inhaler (MDI). The aerosolized droplet sizes were varied by increasing the ethanol co-solvent concentration in the MDI solution. The MDI formulation consists of 1,1,2,2-tetrafluoroethane (HFA-134a), ethanol, and beclomethasone dipropionate (BDP) as the active pharmaceutical ingredient. Since HFA-134a and ethanol are volatile, both substances evaporate rapidly under ambient conditions and trigger condensation of water vapor, increasing the size of aerosols that are predominantly composed of water and BDP. The average deposition fraction in intra-thoracic airways for severe asthmatic subjects with (or without) airway constriction increased from 37%±12 to 53.2%±9.4 (or from 20.7%± 4.6 to 34.7%±6.6) when the ethanol concentration was increased from 1 to 10%wt/wt. However, when the ethanol concentration was further increased from 10 to 20%wt/wt, the deposition fraction decreased. This indicates the importance of selecting appropriate co-solvent amounts during drug formulation development for the treatment of patients with narrowed airway disease. For severe asthmatic subjects with airway narrowing, the inhaled aerosol may benefit from a low hygroscopic effect by reducing ethanol concentration to penetrate the peripheral region effectively. These results could potentially inform the selection of co-solvent amounts for inhalation therapies in a cluster-specific manner.

Development of a mathematical correlation for polydisperse non-spherical drug particle deposition in the human upper respiratory system

Development of a mathematical correlation for polydisperse non-spherical drug particle deposition in the human upper respiratory system

Simulating the effect of individual upper airway anatomical features on drug deposition

This study aims to systematically isolate different anatomical features of the human pharynx with the goal to investigate their independent influence on airflow dynamics and particle deposition characteristics in a geometrically realistic human airway. Specifically, the effects of the uvula, epiglottis and soft palate on drug particle deposition are studied systematically, by carefully removing each of these anatomical features from reconstructed models based on MRI data and comparing them to a benchmark realistic airway model. Computational Fluid Dynamics using established turbulence models is employed to simulate the transport of mono-dispersed particles (3 µm) in the airway at two flow-rates. The simulations suggest three findings: 1) widening the space between the oral cavity and oropharynx and where the soft palate is situated leads to the most dramatic reduction in drug deposition in the upper airway; 2) exclusion of the uvula and epiglottis: a) affects flow dynamics in the airway; b) alters regional deposition behaviour; c) does not significantly affect the total number of particles deposited in the pharynx; and 3) the space adjacent to the soft palate is a key determinant for aerosol deposition in the extrathoracic region and is related to mechanisms of flow acceleration, diversion and recirculation.

An Update on Advancements and Challenges in Inhalational Drug Delivery for Pulmonary Arterial Hypertension.

A lethal condition at the arterial–alveolar juncture caused the exhaustive remodeling of pulmonary arterioles and persistent vasoconstriction, followed by a cumulative augmentation of resistance at the pulmonary vascular and, consequently, right-heart collapse. The selective dilation of the pulmonary endothelium and remodeled vasculature can be achieved by using targeted drug delivery in PAH. Although 12 therapeutics were approved by the FDA for PAH, because of traditional non-specific targeting, they suffered from inconsistent drug release. Despite available inhalation delivery platforms, drug particle deposition into the microenvironment of the pulmonary vasculature and the consequent efficacy of molecules are influenced by pathophysiological conditions, the characteristics of aerosolized mist, and formulations. Uncertainty exists in peripheral hemodynamics outside the pulmonary vasculature and extra-pulmonary side effects, which may be further exacerbated by underlying disease states. The speedy improvement of arterial pressure is possible via the inhalation route because it has direct access to pulmonary arterioles. Additionally, closed particle deposition and accumulation in diseased tissues benefit the restoration of remolded arterioles by reducing fallacious drug deposition in other organs. This review is designed to decipher the pathological changes that should be taken into account when targeting the underlying pulmonary endothelial vasculature, especially with regard to inhaled particle deposition in the alveolar vasculature and characteristic formulations.

Development of a mathematical correlation for polydisperse non-spherical drug particle deposition in the human upper respiratory system

Development of a mathematical correlation for polydisperse non-spherical drug particle deposition in the human upper respiratory system

Regional deposition of the allergens and micro-aerosols in the healthy human nasal airways

The nasal cavity is the inlet to the human respiratory system and is responsible for the olfactory sensation, filtering pollutant particulate matter, and humidifying the air. Many research studies have been performed to numerically predict allergens, contaminants, and/or drug particle deposition in the human nasal cavity; however, the majority of these investigations studied only one or a small number of nasal passages. In the present study, a series of Computed Tomography (CT) scan images of the nasal cavities from ten healthy subjects were collected and used to reconstruct accurate 3D models. All models were divided into twelve anatomical regions in order to study the transport and deposition features of different regions of the nasal cavity with specific functions. The flow field and micro-particle transport equations were solved, and the total and regional particle deposition fractions were evaluated for the rest and low activity breathing conditions. The results show that there are large variations among different subjects. The standard deviation of the total deposition fraction in the nasal cavities was the highest for 5×104<impaction parameter (IP)<1.125×105 with a maximum of 20%. The achieved results highlighted the nasal cavity sections that are more involved in the particle deposition. Particles with IP = 30,000 deposit more in the middle turbinate and nasopharynx areas, while for particles with IP = 300,000, deposition is mainly in the anterior parts (kiesselbach and vestibule regions). For small IP values, the amounts of deposition fractions in different regions of the nasal cavity are more uniform.

Orally Inhaled Drug Particle Transport in Computerized Models of Laryngotracheal Stenosis.

Adjuvant management for laryngotracheal stenosis (LTS) may involve inhaled corticosteroids, but metered dose inhalers are designed for pulmonary drug delivery. Comprehensive analyses of drug particle deposition efficiency for orally inhaled corticosteroids in the stenosis of LTS subjects are lacking. Descriptive research. Academic medical center. Anatomically realistic 3-dimensional reconstructions of the upper airway were created from computed tomography images of 4 LTS subjects-2 subglottic stenosis and 2 tracheal stenosis subjects. Computational fluid dynamics modeling was used to simulate airflow and drug particle transport in each airway. Three inhalation pressures were simulated, 10 Pa, 25 Pa, and 40 Pa. Drug particle transport was simulated for 100 to 950 nanoparticles and 1 to 50 micron-particles. Particles were released into the airway to mimic varying inhaler conditions with and without a spacer chamber. Based on smallest to largest cross-sectional area ratio, the laryngotracheal stenotic segment shrunk by 57% and 47%, respectively, for subglottic stenosis models and by 53% for both tracheal stenosis models. Airflow resistance at the stenotic segment was lower in subglottic stenosis models than in tracheal stenosis models: 0.001 to 0.011 Pa.s/mL vs 0.024 to 0.082 Pa.s/mL. Drug depositions for micron-particles and nanoparticles at stenosis were 0.06% to 2.48% and 0.10% to 2.60% for subglottic stenosis and tracheal stenosis models, respectively. Particle sizes with highest stenotic deposition were 6 to 20 µm for subglottic stenosis models and 1 to 10 µm for tracheal stenosis models. This study suggests that at most, 2.60% of inhaled drug particles deposit at the stenosis. Particle size ranges with highest stenotic deposition may not represent typical sizes emitted by inhalers.

Tinkamo inhaliatoriaus ir vaistų derinio parinkimas – lėtinės obstrukcinės plaučių ligos gydymo pagrindas

Lėtinės obstrukcinės plaučių ligos (LOPL)medikamentinio gydymo pagrindas yra įkvepiamieji bronchus plečiantys vaistai. Tačiau, parenkant gydymą, svarbu ne tik pritaikyti tinkamiausią vaistą arba vaistų derinį, laiku skirti gydymą arba jį intensyvinti, bet ir parinkti pacientui labiausiai tinkamą inhaliatorių. Tiotropio/olodaterolio tyrimai įrodė gydymo deriniu, palyginus sumonoterapija, pranašumą gerinant plaučių funkciją,mažinant simptomus, hiperinfliaciją, didinant fizinį aktyvumą ir ištvermę, retinant LOPL paūmėjimus, patvirtino ankstyvojo gydymo dviejų bronchus plečiančių vaistų deriniu naudą, išlaikė panašų saugumo profilį bei užtikrino geresnę pacientų gyvenimo kokybę. Respimat® smulkią miglą sukuriantis inhaliatorius – tai unikalus prietaisas, generuojantis lėtai judančią, švelnią ir ilgai išliekančią dulksną bei užtikrinantis ypač didelę vaisto dalelių depoziciją smulkiausiuose kvėpavimo takuose bei visą parą trunkančią bronchodiliataciją. Kartotinio naudojimo Respimat®, kurį galima naudoti su šešiais užtaisais, reikšmingai prisideda prie aplinkos taršos mažinimo.

Tinkamo vaistų derinio ir tinkamo inhaliatoriaus parinkimo svarba gydant lėtinę obstrukcinę plaučių ligą

Lėtinės obstrukcinės plaučių ligos medikamentinio gydymo pagrindas yra įkvepiamieji bronchus plečiantieji vaistai. Atlikti klinikiniai tyrimai įrodė, kad įkvepiamieji ilgo veikimo muskarino receptorių blokatoriai (IVMB) ir ilgo veikimo β2 agonistai (IVBA), derinami kartu, yra veiksmingesni nei įprasti trumpo veikimo vaistai, o jų farmakologiniai profiliai veiksmingai vienas kitą papildo. Tačiau be veiksmingo vaistų derinio labai svarbus ir tinkamo inhaliatoriaus parinkimas. Respimat® smulkią miglą formuojantis inhaliatorius – tai unikalus prietaisas, pasižymintis ypač didele vaisto dalelių depozicija net smulkiausiuose kvėpavimo takuose, palyginus su kitais prietaisais.

Helium-Oxygen Mixture Model for Particle Transport in CT-Based Upper Airways.

The knowledge of respiratory particle transport in the extra-thoracic pathways is essential for the estimation of lung health-risk and optimization of targeted drug delivery. The published literature reports that a significant fraction of the inhaled aerosol particles are deposited in the upper airways, and available inhalers can deliver only a small amount of drug particles to the deeper airways. To improve the targeted drug delivery efficiency to the lungs, it is important to reduce the drug particle deposition in the upper airways. This study aims to minimize the unwanted aerosol particle deposition in the upper airways by employing a gas mixture model for the aerosol particle transport within the upper airways. A helium–oxygen (heliox) mixture (80% helium and 20% oxygen) model is developed for the airflow and particle transport as the heliox mixture is less dense than air. The mouth–throat and upper airway geometry are extracted from CT-scan images. Finite volume based ANSYS Fluent (19.2) solver is used to simulate the airflow and particle transport in the upper airways. Tecplot software and MATLAB code are employed for the airflow and particle post-processing. The simulation results show that turbulence intensity for heliox breathing is lower than in the case of air-breathing. The less turbulent heliox breathing eventually reduces the deposition efficiency (DE) at the upper airways than the air-breathing. The present study, along with additional patient-specific investigation, could improve the understanding of particle transport in upper airways, which may also increase the efficiency of aerosol drug delivery.

Sensitivity Analysis and Uncertainty Quantification in Pulmonary Drug Delivery of Orally Inhaled Pharmaceuticals

In spite of widespread use of modeling tools in inhalation dosimetry, it remains difficult to quantify the output uncertainties when subjected to various sources of input variability. This study aimed to develop a computational model that can quantify the input sensitivity and output uncertainty in pulmonary drug delivery by coupling probabilistic analysis package NESSUS with ANSYS Fluent. An image-based mouth-lung model was used to simulate the transport and deposition of drug particles and variability in particle size, density, and inhalation speed were considered. Results show that input variables have different importance levels on the delivered doses to lungs. For a given level of variability, the delivered dose is more sensitive to the variance of particle diameter than that of the inhalation speed and particle density. The range of input scatters has a profound impact on the outcome probability of delivered efficiencies, while the input distribution type (normal vs. log-normal) appears to have an insignificant effect. Despite normal distributions for all input variables, the output exhibits a non-normal distribution. The proposed model in this study allows easy specification of input distributions to conduct multivariable probabilistic analysis of inhalation drug deliveries, which can facilitate more reliable treatment planning and outcome assessment.

Numerical Investigation of Particle Deposition in Human Nasal Cavity for Different Parameters of Spay Device

Whether the drug is successfully transported to the focus area is the key to the treatment of the rhinitis disease. The efficiency of drug delivery is dependent on the design of nasal spray device. A three-dimensional model of nasal cavity was constructed from the head CT image data of a healthy human subject. The deposition of drug particles was simulated numerically by Computational Fluid Dynamics technique. The main variables of the study were the size and density of drug particles, the injecting speed of drugs etc. In conclusion, with the increase of particle intensity and injection speed, the deposition of particles in the affected area trends to increase after first slow decrease.

Empirical modeling of the fine particle fraction for carrier-based pulmonary delivery formulations.

In vitro study of the deposition of drug particles is commonly used during development of formulations for pulmonary delivery. The assay is demanding, complex, and depends on: properties of the drug and carrier particles, including size, surface characteristics, and shape; interactions between the drug and carrier particles and assay conditions, including flow rate, type of inhaler, and impactor. The aerodynamic properties of an aerosol are measured in vitro using impactors and in most cases are presented as the fine particle fraction, which is a mass percentage of drug particles with an aerodynamic diameter below 5 μm. In the present study, a model in the form of a mathematical equation was developed for prediction of the fine particle fraction. The feature selection was performed using the R-environment package “fscaret”. The input vector was reduced from a total of 135 independent variables to 28. During the modeling stage, techniques like artificial neural networks, genetic programming, rule-based systems, and fuzzy logic systems were used. The 10-fold cross-validation technique was used to assess the generalization ability of the models created. The model obtained had good predictive ability, which was confirmed by a root-mean-square error and normalized root-mean-square error of 4.9 and 11%, respectively. Moreover, validation of the model using external experimental data was performed, and resulted in a root-mean-square error and normalized root-mean-square error of 3.8 and 8.6%, respectively.

Fine Particle Profile of Fluticasone Propionate/Formoterol Fumarate Versus Other Combination Products: the DIFFUSE Study

The efficacy of inhaled products is affected by the degree, and potentially the site, of drug particle deposition in the lungs. Lung deposition correlates with the fine particle fraction (FPF; the proportion of dose containing particles <5 μm in aerodynamic diameter). This in vitro study (defining fluticasone propionate/formoterol particulate size [DIFFUSE]) examined the effects of inhalation flow rate on the FPF of the fluticasone propionate/formoterol (FP/FORM) pMDI aerosol compared with three other inhaled corticosteroids/long-acting β2-agonist (ICS/LABA) combination therapies administered by either DPI or pMDI [fluticasone propionate/salmeterol (FP/SAL), budesonide/formoterol (BUD/FORM) and beclometasone dipropionate/formoterol (BDP/FORM)]. Aerodynamic particle size distribution was determined for each product using an 8-stage Andersen Cascade Impactor at two inhalation flow rates: 28.3 and 60.0 L/min. Fine particle dose (mass of dose <5.0 μm) and FPF were calculated as a percentage of the labeled dose for the LABA and ICS of each product at both flow rates. FP/FORM suspension aerosol provided a high and consistent FPF of approximately 40% for the ICS and LABA components at both flow rates. At 28.3 L/min, the FPF of each component of FP/FORM (41.2% and 39.2%) was greater than that of FP/SAL DPI (12.5% and 11.3%), BUD/FORM DPI (8.2% and 6.6%) and BDP/FORM pMDI (28.5% and 26.0%). At 60.0 L/min, the FPFs of the FP/FORM components (43.7% and 42.1%) were greater than those of FP/SAL (17.8% and 14.8%) and BUD/FORM (35.0% and 30.1%), and similar to those of BDP/FORM (43.0% and 39.5%). The FP/FORM suspension aerosol produced a high and consistent FPF of approximately 40% across both flow rates. The consistent FPF in vitro may be predictive of FP/FORM providing more consistent drug dosing in vivo, helping to counteract variable lung dose due to variation in inspiratory flow rate among patients and between a patient’s day-to-day or successive inhalation maneuvers.

Formulation and Evaluation of Insulin Dry Powder for Inhalation

Purpose. Dry powder formulation of insulin for pulmonary administration was prepared to obtain increased drug deposition in the alveolar absorptive region. The deposition was studied by investigating the dispersion and deaggregation of insulin from the carrier lactose using an Andersen cascade impactor and twin stage impinger. The subsequent absorption following the deposition was studied by in vivo method. Methods. Insulin in solution with absorption promoters was lyophilized. The powder was incorporated with lactose of different grades and their combinations as carriers to deliver using an inhaler device. Solid-state characteristics of the carrier as well as the drug powder were assessed by particle size and distribution measurement. The flow properties such as moisture content, powder density, angle of repose, and carr's compressibility index of the powder mixture were determined. The aerosol behavior of the powder was studied by dispersion using rotahaler© connected to a twin-stage impinger (TSI) and an eight-stage Andersen cascade impactor (ACI) operating at different flow rates of 30–90 l/min. The in vivo performance was studied by deliverance to the respiratory tract of guinea pigs. The intratracheal bioavailability with respective to intravenous route was calculated by measuring the blood glucose reduction. Results. The coarser particles of lactose in fractions of carrier containing a wide particle size distribution impacted in the preseperator of cascade impactor, and only the particle less than 10 µm size entered stage 0–stage 7. Formulation containing 1:1 mixture of Respitose ML006 (62%<50 µm) and Respitose ML003 (37.8%<50 µm) as carrier imparts well deaggregation of insulin, and higher deposition leads to 52.3% of fine particle fraction at 60 Lit/min and in vivo bioavailability of 82%. Conclusions. Insulin formulations containing 1:1 mixture of Respitose ML006 and Respitose ML003 as carrier can impart deeper deposition of drug particles and cause higher bioavailability. This suggests that carrier used in the formulation influenced the amount of insulin deposition in the alveolar region of the lung. Hence, it was concluded that the availability of insulin for systemic absorption depends on the particle size of the drug as well as the carrier lactose.