Cell line-based models of normal and chronic bronchitis-like airway mucosa to study the toxic potential of aerosolized palladium nanoparticles.

Background: Physiologically relevant cell line-based models of human airway mucosa are needed to assess nanoparticle-mediated pulmonary toxicity for any xenbiotics expsoure study. Palladium nanoparticles (Pd-NP) originating from catalytic converters in vehicles pose health risks. We aimed to develop airway models to assess the toxic potential of Pd-NP in normal (Non-CB) and chronic bronchitis-like (CB-like) mucosa models.

Integration of mucus and its impact within in vitro setups for inhaled drugs and formulations: Identifying the limits of simple vs. complex methodologies when studying drug dissolution and permeability.

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of 'inhalation biopharmaceutics' i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs.

Regional lung targeting with a fluticasone/salmeterol aerosol using a bolus breath hold method of the PreciseInhale® system: A first evaluation in humans.

Background: In development of inhaled drugs- and formulations the measured concentration in the systemic circulation is often used as a surrogate for local dosimetry in the lungs. To further elucidate regional differences in the fate of drugs in the lungs, different aerodynamic sizes of aerosols have been used to target major airway regions. An alternative approach to achieve regional targeting of aerosols, is to use a defined aerosol bolus together with a bolus breath hold strategy.

Establishment of Repeated In Vitro Exposure System for Evaluating Pulmonary Toxicity of Representative Criteria Air Pollutants Using Advanced Bronchial Mucosa Models.

There is mounting evidence that shows the association between chronic exposure to air pollutants (particulate matter and gaseous) and onset of various respiratory impairments. However, the corresponding toxicological mechanisms of mixed exposure are poorly understood. Therefore, in this study, we aimed to establish a repeated exposure setting for evaluating the pulmonary toxicological effects of diesel exhaust particles (DEP), nitrogen dioxide (NO2), and sulfur dioxide (SO2) as representative criterial air pollutants.

Leucine improves the aerosol performance of dry powder inhaler formulations of siRNA-loaded nanoparticles.

Thermostable dry powder inhaler (DPI) formulations with high aerosol performance are attractive inhalable solid dosage forms for local treatment of inflammatory lung diseases. We recently demonstrated that lipidoid-polymer hybrid nanoparticles (LPNs) loaded with small interfering RNA (siRNA) directed against tumor necrosis factor alpha (TNF-α) mediate efficient intracellular siRNA delivery and reduce inflammation in vivo. Here, we show that mixtures of the stabilizing excipients trehalose (Tre) and dextran (Dex), in combination with the shell-forming dispersion enhancer leucine (Leu), stabilize TNF-α siRNA-loaded LPNs during spray drying into nanocomposite microparticles, and result in DPI formulations with high aerosol performance.

Dry powder inhaler formulation comparison: Study of the role of particle deposition pattern and dissolution.

The composition, morphology and dissolution profile of particles and micro-sized agglomerates delivered upon inhalation may have a significant impact on the product clinical effect. However, although several efforts are ongoing, a methodology that considers deposition structures and dissolution performance evaluation in a biorelevant set-up is not yet standardized. The goal of this work is to apply a collection and dissolution methodology able to discriminate dry powder inhaler (DPI) formulations in terms of deposition structures and dissolution profile in vitro.

Airway Epithelial Lining Fluid and Plasma Pharmacokinetics of Inhaled Fluticasone Propionate and Salmeterol Xinafoate in Mechanically Ventilated Pigs.

The lower respiratory tract of the landrace pig has close anatomical and physiological similarities with that of the human, and hence, for inhalation studies this species is well suited for biopharmaceutical research. The objective of this study was to evaluate pharmacokinetics in pigs following one dose of Diskus™ Seretide™ forte device, labeled 500/50 fluticasone propionate (FP) and salmeterol xinafoate (SX), respectively. The PreciseInhale™ (PI) instrument was used to actuate the inhaler for testing and aerosol dosing to pigs.

Dry Generation of CeO Nanoparticles and Deposition onto a Co-Culture of A549 and THP-1 Cells in Air-Liquid Interface-Dosimetry Considerations and Comparison to Submerged Exposure.

Relevant in vitro assays that can simulate exposure to nanoparticles (NPs) via inhalation are urgently needed. Presently, the most common method employed is to expose lung cells under submerged conditions, but the cellular responses to NPs under such conditions might differ from those observed at the more physiological air-liquid interface (ALI). The aim of this study was to investigate the cytotoxic and inflammatory potential of CeO NPs (NM-212) in a co-culture of A549 lung epithelial cells and differentiated THP-1 cells in both ALI and submerged conditions.

Adapting the Aerogen Mesh Nebulizer for Dried Aerosol Exposures Using the PreciseInhale Platform.

Many substances used in inhalation research are water soluble and can be administered as nebulized solutions. Typical examples are therapeutic, small-molecular agents, or macromolecules. Another category is a number of water-soluble agents used for airway diagnostics or disease modeling.

Exposure of normal and chronic bronchitis-like mucosa models to aerosolized carbon nanoparticles: comparison of pro-inflammatory oxidative stress and tissue injury/repair responses.

Carbon nanoparticles (CNP) are generated by incomplete combustion of diesel engines. Several epidemiological studies associated higher susceptibility to particulate matter related adverse respiratory outcomes with preexisting conditions like chronic bronchitis (CB). Therefore, we compared the effect of CNP exposure on primary bronchial epithelial cells (PBEC) developed in air-liquid interface (ALI) models of normal versus CB-like-mucosa.

Effect of particle deposition density of dry powders on the results produced by an in vitro test system simulating dissolution- and absorption rates in the lungs.

The surface area of the air/liquid interface in the lungs is substantial, so deposited doses of aerosol medicines per interface surface area when administered via the inhalation route is always quite low. However, in most in vitro systems used for dissolution testing of dry powder inhalables, the dose per surface area is generally much higher. The aim of this study was to investigate in one in vitro lung dissolution system, the DissolvIt, the manner in which the deposited dose per test surface area of drug particles influences the simulated dissolution- and absorption rate.

Use of PBPK Modeling To Evaluate the Performance of Dissolv It, a Biorelevant Dissolution Assay for Orally Inhaled Drug Products.

The dissolution of inhaled drug particles in the lungs is a challenge to model using biorelevant methods in terms of (i) collecting a respirable emitted aerosol fraction and dose, (ii) presenting this to a small volume of medium that is representative of lung lining fluid, and (iii) measuring the low concentrations of drug released. We report developments in methodology for each of these steps and utilize mechanistic in silico modeling to evaluate the in vitro dissolution profiles in the context of plasma concentration-time profiles. The PreciseInhale aerosol delivery system was used to deliver Flixotide aerosol particles to Dissolv It apparatus for measurement of dissolution.

Daily intake of phthalates, MEHP, and DINCH by ingestion and inhalation.

Phthalate esters, suspected endocrine disrupting chemicals, are used in a wide range of applications. Because phthalate esters are not covalently bound, they can easily leach into the indoor environment and associate to dust particles. Thus, exposure may occur through inhalation, ingestion, or contact with the skin.

Multi-cellular human bronchial models exposed to diesel exhaust particles: assessment of inflammation, oxidative stress and macrophage polarization.

Background: Diesel exhaust particles (DEP) are a major component of outdoor air pollution. DEP mediated pulmonary effects are plausibly linked to inflammatory and oxidative stress response in which macrophages (MQ), epithelial cells and their cell-cell interaction plays a crucial role. Therefore, in this study we aimed at studying the cellular crosstalk between airway epithelial cells with MQ and MQ polarization following exposure to aerosolized DEP by assessing inflammation, oxidative stress, and MQ polarization response markers.

Effects of tiotropium bromide on airway hyperresponsiveness and inflammation in mice exposed to organic dust.

Introduction: Acute exposure to organic dust (OD) in pig barns induces intense airway inflammation with neutrophilia and hyperresponsiveness. This reaction is likely associated with increased cholinergic activity. Therefore, the involvement of cholinergic mechanisms in the reaction to acute exposure of OD was investigated in mice using the long-acting muscarinic antagonist tiotropium.

Isolation and characterization of a respirable particle fraction from residential house-dust.

Indoor air pollution has caused increasing concern in recent years. As we spend most of our lives indoors, it is crucial to understand the health effects caused by indoor air pollution. Household dust serve as good proxy for accessing indoor air pollution, especially smaller dust particles that can pass into the lungs are of interest.

Investigation of Lung Pharmacokinetic of the Novel PDE4 Inhibitor CHF6001 in Preclinical Models: Evaluation of the PreciseInhale Technology.

Background: Preclinical evaluation of new chemical entities (NCEs) designed to be administered by inhalation route requires lung administration to rodents, especially in the discovery phase. Different administration methods have been used until now, but more efforts are required to obtain controlled and reproducible lung deposition when only small amounts of neat powder material are available.

Methods: The PreciseInhale platform used in the present study enables well-controlled powder aerosol exposures with only small amounts of micronized neat material, providing data on inhalation pharmacokinetic (PK) of NCEs at a very early stage.

DissolvIt: An In Vitro Method for Simulating the Dissolution and Absorption of Inhaled Dry Powder Drugs in the Lungs.

The main purpose of this work was to develop an in vitro method for simulating the dissolution and absorption of inhaled dry powder drugs that also mimics systemic pharmacokinetic data. A second purpose was to evaluate this method. DissolvIt was developed as a simulation of the air-blood barrier of the upper airways, constituting: "airborne" particles deposited on a glass cover slip, a mucus simulant, a polycarbonate (basal) membrane, and a pumped albumin buffer simulating the pulmonary blood flow.

Development of Combining of Human Bronchial Mucosa Models with XposeALI® for Exposure of Air Pollution Nanoparticles.

Background: Exposure to agents via inhalation is of great concerns both in workplace environment and in the daily contact with particles in the ambient air. Reliable human airway exposure systems will most likely replace animal experiment in future toxicity assessment studies of inhaled agents.

Methods: In this study, we successfully established a combination of an exposure system (XposeALI) with 3D models mimicking both healthy and chronic bronchitis-like mucosa by co-culturing human primary bronchial epithelial cells (PBEC) and fibroblast at air-liquid interface (ALI).

Dry powder inhalation exposures of the endotracheally intubated rat lung, ex vivo and in vivo: the pulmonary pharmacokinetics of fluticasone furoate.

Background: The isolated perfused rat lung (IPL) is a suitable model for studying lung-specific pharmacokinetics (PK) of inhaled drugs. So far, little has been known, however, whether the PK measured in the ex vivo organ corresponds to the PK measured in similarly exposed animals in vivo, in particular the endotracheally intubated rat (EIR). The purpose of the current research was to compare the PK of inhaled corticosteroid fluticasone furoate (FF) in the IPL and the EIR.

Solution-engineered palladium nanoparticles: model for health effect studies of automotive particulate pollution.

Palladium (Pd) nanoparticles are recognized as components of airborne automotive pollution produced by abrasion of catalyst materials in the car exhaust system. Here we produced dispersions of hydrophilic spherical Pd nanoparticles (Pd-NP) of uniform shape and size (10.4 ± 2.

Challenges in inhaled product development and opportunities for open innovation.

Dosimetry, safety and the efficacy of drugs in the lungs are critical factors in the development of inhaled medicines. This article considers the challenges in each of these areas with reference to current industry practices for developing inhaled products, and suggests collaborative scientific approaches to address these challenges. The portfolio of molecules requiring delivery by inhalation has expanded rapidly to include novel drugs for lung disease, combination therapies, biopharmaceuticals and candidates for systemic delivery via the lung.

Delivering horseradish peroxidase as a respirable powder to the isolated, perfused, and ventilated lung of the rat: the pulmonary disposition of an inhaled model biopharmaceutical.

Background: Our aim was to investigate the potential of the DustGun aerosol technology integrated with the isolated, perfused, and ventilated lung of the rat (IPL) to study the pulmonary disposition of an inhaled model biopharmaceutical, the 40-kDa protein horseradish peroxidase (HRP).

Method: The DustGun aerosol technology was used to deliver respirable powder aerosols of HRP (the mass median aerodynamic diameter: 1.7 μm) as an 80-sec bolus to the IPL perfused in a single-pass mode.

Vasoconstriction after inhalation of budesonide: a study in the isolated and perfused rat lung.

Introduction: Clinical studies have shown that inhaled corticosteroids can induce rapid vasoconstriction in the airways, leading to decreased mucosal blood flow. The aim of this study was to investigate whether vasoconstriction of the pulmonary circulation after short inhalation of a corticosteroid can be detected in the isolated and perfused rat lung (IPL) - a model which could serve as a substitute or a complement to clinical models.

Methods: IPLs were briefly exposed to dry powder aerosol of budesonide.