Ola Nerbrink

Clearance in smaller airways of inhaled 6-μm particles in subjects with immotile-cilia syndrome

In subjects with an inherited lack of mucociliary transport, so called immotile-cilia syndrome (ICS), coughing effectively clears particles deposited in larger airways of the tracheobronchial region. The present study investigated clearance in smaller airways of 111In-labeled 6-microm (aerodynamic diameter) monodisperse Teflon particles in six subjects with ICS. The particles were inhaled at an extremely slow flow, 0.05 L/s. Theoretical calculations and experimental data in healthy subjects using this slow flow support particle deposition mainly in smaller ciliated airways, i.e., in bronchioli (generations 12-16). This contrasts with the more centrally deposited pattern obtained using a normal inhalation flow, 0.5 L/s. Lung retention was measured at 0, 24, 48,72 and 96 h. Clearance was significant every 24 h measured over the first 72 h, whereupon it slowed down. The fractions of retained particles were significantly (p < .01) larger than those found for healthy subjects using the slow inhalation flow and those found for ICS subjects using a normal inhalation flow. The results indicate that clearance of particles in smaller airways is incomplete and that cough cannot fully compensate for the lack of mucociliary transport in this region.

A Novel Dry Powder Aerosol Delivery System for Real Time Measurement of the Inhaled Dose to Large Animals (Dogs)

ABSTRACT Pharmaceutical drugs can be administered by inhalation to experimental animals as a dry powder aerosol. In such experiments the aerosol is continuously generated from a dry powder generator and inhaled by the experimental animal. The drug delivery system can be used to study the effects of drugs either locally, in the airways and lung, or systemically. With conventional methods, however, it has not been possible to measure the inhaled mass and calculate the accumulated inhaled dose nor to perform the measurements in real time. The method evaluated here, called FIDO, was thus developed to more accurately estimate an inhaled dose than the methods used previously. To validate the feasibility of FIDO, it was compared with two conventional filter methods. Inhalation studies on five dogs were performed at three different aerosol concentrations corresponding to low, medium, and high inhaled doses. The dogs were exposed in a random manner four times at each dose level. In separate studies the generator p...

Human Tracheobronchial Deposition and Effect of Two Cholinergic Aerosols

The effects of two methacholine aerosols with mass median diameters congruent to 7 and 3 microns were measured in 10 healthy subjects. The concentrations of the two aerosols were increased until forced expiratory volume in 1 s (FEV1) decreased with about 20%. Pulmonary fraction (FEV1, FVC, FEV25-75%, FEF75-85%, R(aw), and phase III of single breath O2 test) and deposition of 3.6-microns radiolabeled Teflon particles were studied before and after bronchial challenge with the two aerosols. Output from the nebulizers and size distribution were measured and from these data and from data on deposition of Teflon particles from this and seven earlier studies the doses of the two methacholine aerosols to the tracheobronchial region were calculated. The changes in all pulmonary function parameters and deposition of 3.6-microns particles were similar for the two aerosols. The calculated dose for the aerosol with the large particles was 3-4 times higher than that with the smaller particles. The results indicate greater effect of a certain dose to the tracheobronchial part of the lung if the mass is spread on many small particles than on fewer large ones.

Regional Deposition of Inhaled Evans Blue Dye in Mechanically Ventilated Rabbits with Air or Helium Oxygen Mixture

An animal model has been used and further developed to examine and evaluate differences in regional deposition patterns of an Evans Blue dye (EB) tracer aerosol. This was done by using different carrier gas composition of either He-O2 (80% helium, 20% oxygen) or air (79% nitrogen, 21% oxygen) in histamine-provoked and nonprovoked rabbits. The ratio of peripheral deposition to total deposition (central + peripheral), in relation to percentage increase in intratracheal pressure (ITP delta %), was used as an evaluation tool. The animals were tracheostomized, cannulated, and ventilated in a volume-controlled mode until they were stable. Saline or histamine was then administrated for 2 min before the tracer aerosol EB was given. The percentage increase in intratracheal pressure before and after provocation was calculated (ITP delta %) and was, on average, 51 +/- 20% for air and 51 +/- 20% for He-O2. EB was extracted from lung tissues and measured with a spectrophotometer. The absorbance in different lung regions was used as a measure of the distribution of aerosol. Bronchial provocation gave a central deposition 0.55 +/- 0.11 (mean +/- SD, ratio = peripheral deposition/central + peripheral deposition) compared to 0.80 +/- 0.09 in the control group. He-O2-ventilated rabbits showed significantly higher peripheral deposition ratio (0.67 +/- 0.12) compared with air-ventilated rabbits (0.55 +/- 0.11). The latter finding may be due to the difference in the degree of turbulent flow. There were significant correlations between intratracheal peak pressure and peripheral deposition, r = -.60 and r = -.71 for air and He-O2, respectively. This study demonstrates the possibility of using a rabbit model and different carrier gases for evaluation of effects of bronchial provocation.

Selective aerosol delivery to intubated rats; a comparison with nose only exposure

Abstract A new aerosol delivery system, which leads the aerosol directly to the lung via an endotracheal tube (under anaesthesia), bypassing the upper respiratory tract has been characterized. Animals can be repeatedly treated for study of drug effects in models of asthma. The amount Evans blue deposited in the lung with nebulized Evans blue dye was 12 μg which is 8% of the filter amount (158 μg, filter sampling 0.2 L/min, 5 min exposure). The distribution within the lung was 10% to 20% in the central airways and the rest in the peripheral part of the lung, regardless of whether or not the rats were being exposed nose only or via the endotracheal tube. No significant weight changes on stress sensitive organs were seen.

Aerosol Delivery to the Respiratory tract in Experimental Animals

The inhaled route is a convenient way to deliver drugs to the lung. Inhaled pharmaceutical drugs can either act locally in the lung or get absorbed into the systemic circulation to exert their effect. Since the lung functions as a filter it is important to know the optimal particle size distribution to get an optimal deposition in the lung for the species to be studied. In the search for better drugs for local treatment of inflammatory diseases in the respiratory tract it is important that new candidate drugs are evaluated in inhalation delivery systems that are well characterised. Aerosols can be delivered either nose-only or by intubating rats or dogs. An aerosol generator can be fitted to the inhalation chamber or to the nose mask which allows for the aerosol to be inhaled. Selective aerosol deposition in the lung can be achieved by use of the endotracheal tube. In both the above cases, the inhaled dose can be calculated from a filter sample drawn in the breathing zone of the animal during exposure. Simultaneously the aerosol can be monitored in real-time to measure changes in the particle concentration. This is an advantage as the aerosol concentration can be adjusted during delivery to give a more accurate dose to the animal. In our exposure systems, a tracer aerosol with Evans blue, is used to verify the estimated lung burden with the actual deposition patterns found in these animals. Finally we will also give an example of how the effect/side effects ratio can vary if a glucocorticosteroid (budesonide) is administered by different routes, and how the estimated inhaled dose correlates with the kinetic profile (area under the curve).

Comparison of ISO standards for device performance; 20072 and 27427: a critical appraisal.

Two separate international standards, ISO 20072:2009 and ISO 27427:2010, have recently been published that relate to the development and performance testing of oral inhaled products (OIPs). The scope of ISO 20072 encompasses all OIP forms except nebulizing systems, whereas ISO 27427 was developed specifically for this class of OIP. Compliance with these standards will likely be necessary for manufacturers seeking approval to market inhaler devices in the European Union (EU). Their adoption in the United States may take a considerable time, but the FDA has expressed support in general terms for the ISO process. Key aspects of both standards that are very different in style and content are identified and discussed from the perspective of a potential user. In the approach adopted by ISO 20072, a formalized risk assessment is undertaken as a key part of design verification, in order to develop the Device Functionality Profile (DFP) of the device. The DFP is subsequently verified by the System Verification Test (SVT), in which pharmacopeial test methods are used to evaluate in vitro performance of the device with a chosen drug product in a statistically robust manner. On the other hand, ISO 27427 adopts a more prescriptive approach that involves performance verification of the finished nebulizing system using 1% w/v salbutamol as the test formulation. Although ISO 27427 is currently undergoing revision, at present it is unclear whether the changes that are made will significantly alter its fundamentally different approach to device performance verification. A strong case can be made for a single OIP-wide ISO standard, based on the principles developed in ISO 20072 and that makes use of the well-understood and validated in vitro test procedures that are available or will shortly be available in the case of nebulizing systems, in the United States and European pharmacopeias.

A new aerosol delivery system to dogs

Abstract We have developed an aerosol delivery system to dogs based on breath actuated nebulization. The deposited dose of 99m Tc-DTPA to the dog lungs was less than 10% after mouth breathing and increased at nose breathing to 31% and 52% for the two dogs. After 10 min inhalation a dose of 2 mg terbutaline was deposited in the respiratory tract, based on pharmacokinetic calculations. This aerosol delivery system can be used in pharmacological and toxicological studies when new drugs need to be tested by the inhaled route.